Analogs of Ghrelin

ABSTRACT

The invention comprises peptidyl analogs according to formulae (I) or (II) as depicted below: 
                 (R 2 R 3 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -           A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -           A- 26 -A 27 -A 28 -R 1                     
wherein the definitions of A 1  to A 28  and R 1  to R 3  are provided for in the specification for each of formulae (I) and (II), pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising an effective amount of a compound of formula (I), that possess agonist or antagonist ghrelin activity, along with therapeutic and non-therapeutic uses thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of copending international(PCT) application No. PCT/US2006/037889, filed Sep. 27, 2006,designating the United States, which application claims priority to U.S.provisional application Nos. 60/750,771, filed Dec. 15, 2005;60/748,904, filed Dec. 19, 2005; and 60/721,557, filed Sep. 28, 2005.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to peptidyl analogs that possess agonist orantagonist ghrelin activity and their therapeutic use thereof.

2. Description of the Prior Art

Ghrelin, a recently discovered orexigenic hormone, is produced as apreprohormone that is proteolytically processed to yield a peptide ofthe following sequence:H-Gly-Ser-Ser-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg-NH₂(Kojima, M. et al., Nature, (1999), 402(6762):656-60). Ghrelin isproduced by epithelial cells lining the fundus of the stomach andfunctions to stimulate appetite; its levels increase prior to a meal anddecrease thereafter.

The native structures of ghrelin from several mammalian andnon-mammalian species are known (Kaiya, H. et al., J. Biol. Chem.,(2001), 276(44):40441-8; and International Patent ApplicationPCT/JP00/04907 [WO 01/07475]). A core region present in ghrelin isresponsible for activity observed at the GHS receptor which comprisesthe four N-terminal amino acids wherein the serine in the third positionis normally modified with n-octanoic acid. In addition to acylation byn-octanoic acid, native ghrelin may also be acylated with n-decanoicacid (Kaiya, H. et al., J. Biol. Chem., (2001), 276(44):40441-8).

Ghrelin levels in the plasma of obese individuals are lower than thosein leaner individuals and levels of ghrelin increase during the time ofthe day from midnight to dawn in thinner individuals suggesting a flawin the circulatory systems of obese individuals (Yildiz, B. O. et al.,Proc. Natl. Acad. Sci. USA, (2004), 101(28):10434-9). It has been foundthat individuals suffering from the eating disorder anorexia nervosa andpatients who have cancer-induced cachexia have higher plasma levels ofghrelin (Garcia, J. M. et al., J. Clin. Endocrin. Metab., (2005),90(5):2920-6).

In both animals and in humans, ghrelin powerfully stimulates growthhormone (GH) secretion from the anterior pituitary gland, mainly at thehypothalamic level, through its interaction with the GH secretagogue(GHS) receptor (GHS-R) (Ukkola, O. et al., Ann. Med., (2002),34(2):102-8; and Kojima, M. et al., Nature, (1999), 402(6762):656-60).The GH-releasing activity of ghrelin is mediated by activation of GHSreceptors at the pituitary and mainly at the hypothalamic level (Kojima,M. et al., Nature, (1999), 402(6762):656-60).

Prior to the discovery that ghrelin is a native ligand for the GHSreceptor, it was known that the pulsatile release of GH from thepituitary somatotrops is regulated by two hypothalamic neuropeptides:GH-releasing hormone (GHRH) and somatostatin. GHRH stimulates therelease of GH whereas somatostatin inhibits the secretion of GH(Frohman, L. A. et al., Endocr. Rev., (1986), 7(3):223-53; and Strobl,J. S. et al., Pharmacology Review (1994) 46:1-34). Ghrelin likelyenhances the activity of GHRH-secreting neurons while concomitantlyacting as a functional somatostatin antagonist (Ghigo, E. et al., Eur.J. Endocri., (1997), 136(5):445-60).

Release of GH from the pituitary somatotrops can also be controlled byGH-releasing peptides (GHRP). The hexapeptideHis-D-Trp-Ala-Trp-D-Phe-Lys-amide (GHRP-6) was found to release GH fromthe somatotrops in a dose-dependent manner in several species, includingman (Bowers, C. Y. et al., Endocrinology, (1984), 114(5):1537-45).Subsequent chemical studies on GHRP-6 led to the identification of otherpotent, synthetic GH secretagogues such as GHRP-I, GHRP-2 and hexarelin(Cheng, K. et al., Endocrinology, (1989), 124(6):2791-8; Bowers, C. Y.,Novel GH-Releasing Peptides, Molecular and Clinical Advances inPituitary Disorders, Ed: Melmed, S., Endocrine Research and Education,Inc., Los Angeles, Calif., USA, (1993), 153-7; and Deghenghi, R. et al.,Life Sci., (1994), 54(18):1321-8). The structures of these threecompounds are:

GHRP-I Ala-His-D-(2′)-Nal-Ala-Trp-D-Phe-Lys-NH₂; GHRP-2D-Ala-D-(2′)-Nal-Ala-Trp-D-Nal-Lys-NH₂; and HexarelinHis-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH₂.

A GHS can stimulate secretion of GH by a different mechanism than thatof GHRH (Bowers, C. Y. et al., Endocrinology, (1984), 114(5):1537-45;Cheng, K. et al., Endocrinology, (1989), 124(6):2791-8; Bowers, C. Y.,Novel GH-Releasing Peptides, Molecular and Clinical Advances inPituitary Disorders, Ed: Melmed, S., Endocrine Research and Education,Inc., Los Angeles, Calif., USA, (1993), 153-7; and Deghenghi, R. et al.,Life Sci., (1994), 54(18):1321-8).

The low oral bioavailability (<1%) of a peptidyl GHS encouraged thesearch for non-peptide compounds mimicking the action of GHRP-6 in thepituitary. Several benzolactams and spiroindanes have been reported tostimulate GH release in various animal species, including humans (Smith,R. G. et al., Science, (1993), 260(5114):1640-3; Patchett, A. A. et al.,Proc. Natl. Acad. Sci. USA, (1995), 92(15):7001-5; Chen, M.-H. et al.,Bioorg. Mod. Chem. Letts., (1996), 6(18):2163-8). A specific example ofa small spiroindane is MK-0677 (Patchett, A. A. et al., Proc. Natl.Acad. Sci. USA, (1995), 92(15):7001-5):

The actions of a GHS (both peptide and non-peptide) appear to bemediated by a specific receptor (Howard, A. D. et al., Science, (1996),273(5277):974-7; and Pong, S. S. et al., Mol. Endocri., (1996),10(1):57-61). This receptor is present in the pituitary and hypothalamusof various mammalian species (GHSR1a) and is distinct from theGH-releasing hormone receptor. The GHS receptor was also detected in theother areas of the central nervous system and in peripheral tissues, forinstance, adrenal, thyroidal, cardiac, pulmonary, renal and muscular(Chen, M.-H. et al., Bioorg. Med. Chem. Letts., (1996), 6(18):2163-9;Howard, A. D. et al., Science, (1996), 273(5277):974-7; Pong, S. S. etal., Mol. Endocri., (1996), 10(1):57-61; Guan, X.-M. et al., Mol. Brain.Res., (1997), 48(1):23-9; and McKee, K. K. et al., Genomics, (1997),46(3):426-34). A truncated version of GHSR1a has been reported (Howard,A. D. et al., Science, (1996), 273(5277):974-7).

The GHS receptor is a G-protein coupled-receptor. The effects of GHSreceptor activation include depolarization and inhibition of potassiumchannels, an increase in intercellular concentrations of inositoltriphosphate (IP3) and a transient increase in the concentrations ofintracellular calcium (Pong, S. S. et al., Mol. Endocri., (1996),10(1):57-61; Guan, X.-M. et al., Mol. Brain. Res., (1997), 48(1):23-9;and McKee, K. K. et al., Genomics, (1997), 46(3):426-34).

GHS molecules such as ghrelin and its analogs have a variety ofdifferent therapeutic (U.S. Pat. No. 6,566,337; Inui, A., FASEB J.,(2004), 18(3):439-56; Muller, E. E. et al., Neurobiol. Aging, (2002),23(5):907-19; Casanueva, F. F. et al., Trends Endocrinol. Metab.,(1999), 10(1):30-8; and Ankerson, M. et al., Drug Discovery Today,(1999), 4:497-506) and diagnostic uses. Compounds exhibiting agonisteffects at the GHS receptor are indicated for improving a GH-deficientstate (U.S. Pat. Nos. 6,861,409 and 6,967,237; and Casanueva, F. F. etal., Trends Endocrinol. Metab, (1999), 10(1):30-8), increasing musclemass (U.S. Pat. Nos. 6,861,409 and 6,967,237) and/or physical strength(Ankerson, M. et al., Drug Discovery Today, (1999), 4:497-506),improving bone density (U.S. Pat. Nos. 6,861,409, 6,967,237 and6,251,902; and Sibilia, V. et al., Growth Horm. IGF Res., (1999),9(4):219-27), treating osteoporosis (International Patent ApplicationNos. PCT/IB96/01353 [WO 97/24369] and PCT/IB98/00873 [WO 98/58947]; andCasanueva, F. F. et al., Trends Endocrinol. Metab., (1999), 10(1):30-8),overcoming sexual dysfunction (U.S. Pat. No. 6,967,237; and Casanueva,F. F. et al., Trends Endocrinol. Metab., (1999) 10(1):30-8), treatingcardiovascular disease (International Patent Application Nos.PCT/IB96/01353 [WO 97/24369] and PCT/IB98/00873 [WO 98/58947]; U.S. Pat.No. 6,251,902; De Gennaro Colonna, V. et al., Eur. J. Pharmacol.,(1997), 334(2-3):201-7; and Casanueva, F. F. et al., Trends Endocrinol.Metab., (1999), 10(1):30-8), relieving arthritis pain (Granado, M., Am.J. Endo. Metab., (2005), 288:486-92), preventing or alleviating theonset of Alzheimer's disease (U.S. Pat. Nos. 6,686,359 and 6,566,337)and/or treating systemic lupus erythematosus or inflammatory boweldisease, e.g. Crohn's disease or ulcerative colitis (U.S. PatentPublication No. 2002/0013320).

Agonistic analogs of ghrelin can facilitate a gain in body weight (U.S.Pat. No. 6,967,237; Tschop, M. et al., Nature, (2000), 407(6806):908-13;and Tschop, M. et al., Endocrinology, (2002), 143(2):558-68) which inturn can be used to maintain a desired body weight (U.S. Pat. Nos.6,861,409 and 6,967,237) and/or to recover physical function (U.S. Pat.Nos. 6,967,237 and 6,251,902; and International Patent Application No.PCT/IB96/01353 [WO 97/24369]).

Ghrelin also increases appetite (U.S. Pat. No. 6,967,237; and Okada, K.et al., Endocrinology, (1996), 137(11):5155-8). As such, ghrelin isoften used to treat patients suffering from certain diseases ordisorders or undertaking medicinal regimens which are traditionallyaccompanied with an undesirable weight loss such as: anorexia (U.S. Pat.No. 6,967,237; and Tschop, M. et al., Endocrinology, (2002),143(2):558-68), bulimia (U.S. Pat. No. 6,967,237), cachexia (U.S. Pat.Nos. 6,967,237 and 6,251,902), particularly cancer-induced cachexia(U.S. Pat. No. 6,967,237; International Patent Appln. No.PCT/DK2004/000529 [WO 05/014032]; and Tschop, M. et al., Endocrinology,(2002), 143:558-68), AIDS (U.S. Pat. Nos. 6,861,409 and 6,967,237; andTschop, M. et al., Endocrinology, (2002), 143(2):558-68), wastingsyndrome in the frail and/or elderly (U.S. Pat. Nos. 6,861,409 and6,967,237; International Patent Application No. PCT/IB96/01353 [WO97/24369]; and Ankerson, M. et al., Drug Discovery Today, (1999)4:497-506) and chronic renal failure (Casanueva, F. F. et al., TrendsEndocri. Metab., (1999), 10(1):30-8). Medicinal treatments traditionallyaccompanied by a weight loss include chemotherapy, radiation therapy,temporary or permanent immobilization and/or dialysis (U.S. Pat. Nos.6,967,237 and 6,251,902).

Obesity is a major risk factor for diabetes and a large fraction ofnon-insulin-dependent diabetes mellitus (otherwise referred to as“NIDDM”) patients are obese. Both conditions are characterized byelevated circulating insulin levels and suppressed GH levels. GHtreatment of GH-deficient adults (Jorgensen, J. O. et al., Lancet,(1989), 1(8649):1221-5), obese women (Richelsen, B. et al., Am. J.Physiol., (1994), 266(2 Pt 1):E211-6) and elderly men (Rudman, D. etal., Horm. Res., (1991), 36 (Suppl 1):73-81) has been shown to produceincreases in lean body, hepatic and muscle mass while decreasing fatmass. Accordingly, administration of a ghrelin agonist is an attractivetherapy for obesity except for the diabetogenic effects of GH (U.S. Pat.No. 6,251,902; Ankerson, M. et al., Drug Discovery Today, (1999)4:497-506; and Casanueva, F. F. et al., Trends Endocri. Metab., (1999),10(1):30-8). Complications of diabetes such as retinopathy and/or fortreating cardiovascular disorders (U.S. Pat. No. 6,967,237; and U.S.Patent Application Publication No. 2003/0211967) may be indirectlytreated by ghrelin as well.

Paradoxically, ghrelin antagonists can be used to facilitate weight lossin an obese individual wherein said obesity is not due to the onset ofNIDDM (U.S. Pat. No. 6,967,237; and U.S. Patent Application PublicationNo. 2003/0211967) as well as several other identified indications.Compounds exhibiting antagonist effects at the GHS receptor to promotethe suppression of GH secretion, e.g., antagonist analogs of ghrelin,are indicated to reverse excessive GH secretion (U.S. Patent ApplicationPublication No. 2002/0187938), to facilitate weight loss in thenon-obese (U.S. Pat. No. 6,967,237), to maintain an ideal weight and/orto decrease appetite (U.S. Pat. No. 6,967,237). Excessive weight is acontributing factor to many diseases or conditions such as hypertension,dyslipidemia and cardiovascular disease (U.S. Patent ApplicationPublication No. 2003/0211967; and U.S. Pat. No. 6,967,237) as well asgall stones, osteoarthritis (U.S. Pat. No. 6,967,237), certain cancers(U.S. Patent Application Publication Nos. 2003/0211967 and 2004/0157227;and U.S. Pat. No. 6,967,237) and Prader-Willi syndrome (U.S. Pat. No.6,950,707; International Patent Application No. PCT/US2004/008385 [WO04/084943]; Haqq, A. M. et al., J. Clin. Endocri. Metab., (2003),88(1):174-8; and Cummings, D. E. et al., Nat. Med., (2002), 8(7):643-4).Ghrelin antagonists which facilitate weight loss would therefore reducethe likelihood of such diseases or conditions and/or comprise at leastpart of a treatment for such diseases or conditions. Antagonists of GHSmolecules have also been disclosed to exhibit binding to tumorigenictissue to result in a decrease in the number of tumorigenic cells in thetarget tissues, e.g. tumors in the lung, mammary glands, thyroid orpancreas (International Patent Application No. PCT/EP99/08662 [WO00/29011]).

Analogs of GH secretagogues have also been employed to promotegastrointestinal motility, particularly in patients suffering fromdecreased gastrointestinal motility resulting from post-operative ileusor from gastroparesis incidental to the onset of diabetes or a chronicdiabetic state (U.S. Pat. No. 6,548,501).

In addition, ghrelin has been effective in treating inflammation in amammalian subject (International Patent Application No.PCT/US2005/016565 [WO 2005/110463]). In particular, the inflammation canbe associated with a viral, bacterial, parasitic or fungal infection.Viral infections treatable with ghrelin may include Herpes simplex virustype-1, Herpes simplex virus type-2, Cytomegalovirus, Epstein-Barrvirus, Varicella-zoster virus, Human herpesvirus 6, Human herpesvirus 7,Human herpesvirus 8, Variola virus, Vesicular stomatitis virus,Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis Dvirus, Hepatitis E virus, Rhinovirus, Coronavirus, Influenza virus A,Influenza virus B. Measles virus, Polyomavirus, Human Papilomavirus,Respiratory syncytial virus, Adenovirus, Coxsackie virus, Dengue virus,Mumps virus, Poliovirus, Rabies virus, Rous sarcoma virus, Yellow fevervirus, Ebola virus, Marburg virus, Lassa fever virus, Eastern EquineEncephalitis virus, Japanese Encephalitis virus, St. Louis Encephalitisvirus, Murray Valley fever virus, West Nile virus, Rift Valley fevervirus, Rotavirus A, Rotavirus B, Rotavirus C, Sindbis virus, SimianImmunodeficiency virus, Human T-cell Leukemia virustype-1, Hantavirus,Rubella virus, Simian Immunodeficiency virus, Human Immunodeficiencyvirus type-1 and Human Immunodeficiency virus type-2. (InternationalPatent Application No. PCT/US2005/016565 [WO 2005/110463]). Bacterialinfections that cause inflammation that can be treated with ghrelin(International Patent Application No. PCT/US2005/016565 [WO2005/110463]) include M. tuberculosis, M bovis, M. bovis strain BCG, BCGsubstrains, M. avium, M intracellulare, M africanum, M kansasii, Mmarinum, M ulcerans, M. avium subspecies paratuberculosis, Nocardiaasteroides, other Nocardia species, Legionella pneumophila, otherLegionella species, Salmonella typhi, other Salmonella species, Shigellaspecies, Yersinia pestis, Pasteurella haemolytica, Pasteurellamultocida, other Pasteurella species, Actinobacillus pleuropneumoniae,Listeria monocytogenes, Listeria ivanovii, Brucella abortus, otherBrucella species, Cowdria ruminantium, Chlamydia pneumoniae, Chlamydiatrachomatis, Chlamydia psittaci, Coxiella burnetti, other Rickettsiaspecies, Ehrlichia species, Staphylococcus aureus, Staphylococcusepidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Bacillusanthracis, Escherichia coli, Vibrio cholerae, Campylobacter species,Neiserria meningitidis, Neiserria gonorrhea, Pseudomonas aeruginosa,other Pseudomonas species, Haemophilus influenzae, Haemophilus ducreyi,other Hemophilus species, Clostridium tetani, other Clostridium species,Yersinia enterolitica and other Yersinia species (International PatentApplication No. PCT/US2005/016565 [WO 2005/110463]).

Inflammation treatable with ghrelin (International Patent ApplicationNo. PCT/US2005/016565 [WO 2005/110463]) can also be caused by parasitesincluding Toxoplasma gondii, Plasmodium, Trypanosoma brucei, Trypanosomacruzi, Leishmania, Schistosoma and Entamoeba histolytica or fungi suchas Candida albicans, Cryptococcus neoformans, Histoplama capsulatum,Aspergillus fumigatus, Coccidiodes immitis, Paracoccidiodesbrasiliensis, Blastomyces dermitidis, Pneomocystis carnii, Penicilliummarneffi and Alternaria alternate (International Patent Application No.PCT/US2005/016565 [WO 2005/110463]).

Inflammation caused by liver toxicity or transplant rejection is alsotreatable by ghrelin (International Patent Application No.PCT/US2005/016565 [WO 2005/110463]). The liver toxicity may beassociated with cancer therapy. In some instances, the cancer therapy,such as chemotherapy, may bring about liver toxicity. Liver toxicitybrought about by both chemotherapy and apoptosis may be treatable byadministration of ghrelin, ghrelin agonists or ghrelin antagonists(International Patent Application No. PCT/US2005/016565 [WO2005/110463]).

Inflammation associated with cancer is also treatable with ghrelin(International Patent Application No. PCT/US2005/016565 [WO2005/110463]). Such cancers include lymphoma, leukemia, mycosisfungoide, carcinoma, adenocarcinoma, sarcoma, glioma, blastoma,neuroblastoma, plasmacytoma, histiocytoma, melanoma, adenoma, hypoxictumor, myeloma, AIDS-related lymphoma or AIDS-related sarcoma,metastatic cancer, bladder cancer, brain cancer, nervous system cancer,glioblastoma, ovarian cancer (International Patent Application No.PCT/AU02/00582 [WO 02/090387]; and Gaytan, F. et al., J. Clin. Endocri.Metab., (2005), 90(3):1798-804), skin cancer, liver cancer, squamouscell carcinomas of the mouth, throat, larynx, and lung, colon cancer,cervical cancer (International Patent Application No. PCT/AU02/00582 [WO02/090387]), breast cancer (International Patent Application No.PCT/AU02/00582 [WO 02/090387]; and Cassoni, P. et al., J. Clin. Endocri.Metab., (2001), 86(4):1738-45), epithelial cancer, renal cancer(Jungwirth, A. et al., Proc. Natl. Acad. Sci. USA, (1997),94(11):5810-3), genitourinary cancer, pulmonary cancer (Ghé, C. et al.,Endocrinology, (2002), 143(2):484-91), esophageal carcinoma (Nwokolo, C.U. et al., Gut, (2003), 52(5):637-40), head and neck carcinoma (Jozkow,P. et al., Head Neck, (2005), 27(3):243-7), hematopoietic cancer,testicular cancer (Gaytan, F. et al., J. Clin. Endocri Metab., (2004),89(1):400-9), colo-rectal cancer (Dagnaes-Hansen, H. et al., AnticancerRes., (2004), 24(6):3735), prostatic cancer (Jeffery, P. L. et al.,Endocrinology, (2002), 172:R7-11), and pancreatic cancer (Volante, M. etal., J. Clin. Endocri. Metab., (2002), 87(3):1300-8); and InternationalPatent Application No. PCT/US2005/016565 [WO 2005/110463]).

Finally, ghrelin has been shown to treat inflammatory diseases(International Patent Application No. PCT/US2005/016565 [WO2005/110463]) such as asthma, reactive arthritis, hepatitis (Wallace, J.D. et al., J. Clin. Endocri. Metab., (2002), 87(6):2751-9),spondyarthritis, Sjogren's syndrome, Alzheimer's disease (U.S. Pat. Nos.6,686,359 and 6,566,337; and Obermayr, R. P. et al., Gerontology,(2003), 49(3):191-5), and atopic dermatitis or inflammatory diseasesassociated with an autoimmune disease such as systemic lupuserythematosus, rheumatoid arthritis (Otero, M. et al., Rheumatology(Oxford), (2004), 43(3):306-10), systemic vasculitis, insulin dependentdiabetes mellitus (Nieves-Riviera, F. et al., Growth Regul., (1993),3:235-44), multiple sclerosis and muscular dystrophy (U.S. PatentPublication No. 2003/0139348), experimental allergic encephalomyelitis(Ikushima, H. et al., J. Immunol., (2003), 171:2769-72), psoriasis(Edmondson, S. R. et al., Endocri. Rev., (2003), 24(6):737-64), Crohn'sdisease (Slonim, A. E. et al., N. Engl. J. Med., (2000),342(22):1633-7), inflammatory bowel disease (Chen, K. et al., Surgery,(1997), 121(2):212-8), ulcerative colitis, Addison's disease (Arvat, E.et al., Neuroendocrinology, (1999), 70(3):200-6), alopecia aretea,celiac disease (Peracchi, M. et al., Am. J. Gastroenterol., (2003),98(11):2474-8); and Capristo, E. et al., Scand. J. Gastroenterol.,(2005), 40(4):430-6), thyroid disease (Riis, A. L. et al., J. Clin.Endocrin. Metab., (2003), 88(2):853-7), and scleroderma. Inflammation asa result of a burn may also benefit from treatment with ghrelin as mayinflammation of the lung (International Patent Application No.PCT/US2005/016565 [WO 2005/110463]). Inflammation may also cause asubject to lose appetite, particularly when the inflammation is lowgrade and/or in an aging subject (International Patent Application No.PCT/US2005/016565 [WO 2005/110463]).

Ghrelin antagonists can also be used to achieve a beneficial effect in apatient (U.S. Patent Publication Nos. 2002/187938, 2003/0211967 and2004/0157227; and U.S. Pat. No. 6,967,237). For example, a ghrelinantagonist can be used to facilitate weight loss or decrease inappetite, to maintain an ideal body weight, to treat obesity, to managea diabetic state including complications thereof such as retinopathy,and/or to treat cardiovascular disorders. Excessive weight is acontributing factor of several diverse diseases or conditions including,but not limited to, hypertension, diabetes, dyslipidemia, cardiovasculardisease, gall stone formation, osteoarthritis and Prader-Willi syndromeas well as certain forms of cancers. Bringing about a weight loss can beused, for example, to reduce the likelihood of such diseases and as partof a treatment for such diseases.

Given the wide variety of beneficial effects that GHSs have to offer,there is a need in the art for effective agonist or antagonist ghrelinanalog molecules.

SUMMARY OF THE INVENTION

It was discovered that ghrelin analogs in which the amino acids atresidues A¹⁵, A¹⁶, A¹⁷, A¹⁸, A¹⁹ or A²⁰ were substituted with eitherAsp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷),Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹¹), Glu(NH—R⁷), Glu(O—R⁶), Gly(myristyl),Ser(C(O)—R⁴), Thr(C(O)—R⁵) or HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O), or, inparticular, Lys(biotinyl)¹⁷ or Lys(myristyl)¹⁷, exhibited higher cellmembrane binding affinity and were found to interact more efficientlywith membrane bound receptors and thus were more biologically potentcompared to native ghrelin.

In light of this finding, the present invention features ghrelin analogsactive at the GHS receptor in which amino acids at residues A¹⁵, A¹⁶,A¹⁷, A¹⁸, A¹⁹ or A²⁰ are substituted with either Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷, Glu(O—R⁶), Gly(myristyl)¹, Lys(biotinyl)¹⁷,Lys(myristyl)¹⁷, Ser(C(O)—R⁴), Thr(C(O)—R⁵) orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O).

Thus, a first aspect of the present invention describes a ghrelin analogaccording to formula (I), wherein the first amino acid listed in thedefinitions of A¹ to A²⁸ is the amino acid found at that position in thesequence of native ghrelin, i.e.H-Gly-Ser-Ser-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg-NH₂:

(R²R³)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵- A²⁶-A²⁷-A²⁸-R¹ (I)wherein:

A¹ is Gly, Acc, Aib, Ala or β-Ala;

A² is Ser, Abu, Acc, Act, Aib, Ala, Ava, Thr or Val;

A³ is Ser, Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O);

A⁴ is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal,hPhe, (X¹,X²,X³,X⁴,X⁵)Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr;

A⁵ is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle orVal;

A⁶ is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;

A⁷ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;

A⁸ is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O);

A⁹ is His, Acc, Apc, Aib, 2-Fua, 2-Pal, 3-Pal, 4-Pal,(X¹,X²,X³,X⁴,X⁵—)Phe, Taz, 2-Thi or 3-Thi;

A¹⁰ is Gln, Acc, Aib, Asn, Asp or Glu;

A¹¹ is Arg, Apc, hArg, Dab, Dap, Lys, Orn orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O);

A¹² is Val, Abu, Acc, Aib, Ala, Cha, Gly, Ile, Leu, Nle, Nva or Tle;

A¹³ is Gln, Acc, Aib, Asn, Asp or Glu;

A¹⁴ is Gln, Acc, Aib, Asn, Asp or Glu;

A¹⁵ is Arg, Acc, Aib, Apc, hArg, Dab, Dap, Lys, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷, Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O);

A¹⁶ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R⁷),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A¹⁷ is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Lys(biotinyl), Ser(C(O)—R⁴),Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A¹⁸ is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val, Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A¹⁹ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A²⁰ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷, Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A²¹ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic ordeleted;

A²² is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic ordeleted;

A²³ is Abu, Acc, Act, Aib, Ala, Apc, Gly, Nva, Val or deleted;

A²⁴ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn,HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A²⁵ is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Valor deleted;

A²⁶ is Gln, Aib, Asn, Asp, Glu or deleted;

A²⁷ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic ordeleted;

A²⁸ is Acc, Aib, Apc, Arg, hArg, Dab, Dap, Lys, Orn,HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

R¹ is —OH, —NH₂, —(C₁-C₃₀)alkoxy or NH—X⁶—CH₂-Z⁰, wherein X⁶ is a(C₁-C₁₂)alkyl or (C₂-C₁₂)alkenyl and Z⁰ is —H, —OH, —CO₂H or —C(O)—NH₂;

each of R² and R³ is, independently for each occurrence thereof,selected from the group consisting of H, (C₁-C₃₀)alkyl,(C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl,aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)alkyl,substituted (C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)acyl, substituted(C₂-C₃₀)alkenyl, substituted aryl(C₁-C₃₀)alkyl, substituted(C₂-C₃₀)alkynyl and substituted aryl(C₁-C₃₀)acyl;

each of R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴R¹⁵, R¹⁶ and R¹⁷ is,independently for each occurrence thereof, selected from the groupconsisting of (C₁-C₄₀)alkyl, (C₂-C₄₀)alkenyl, substituted (C₁-C₄₀)alkyl, substituted (C₂-C₄₀) alkenyl, alkylaryl, substituted alkylaryl,aryl and substituted aryl;

each of R¹² and R¹³ is, independently for each occurrence, selected fromthe group consisting of H, (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl,(C₁-C₄₀)acyl, (C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl, aryl(C₁-C₄₀)alkyl,aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)alkyl, substituted(C₁-C₄₀)heteroalkyl, substituted (C₁-C₄₀)acyl, substituted(C₂-C₄₀)alkenyl, substituted (C₂-C₄₀)alkynyl, substitutedaryl(C₁-C₄₀)alkyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl,—C(NH)—NH₂ and biotinyl;

n is, independently for each occurrence thereof, 1, 2, 3, 4 or 5;

each of X¹, X², X³, X⁴, and X⁵ is, independently for each occurrencethereof, selected from the group consisting of H, F, Cl, Br, I,(C₁₋₁₀)alkyl, substituted (C₁₋₁₀)alkyl, aryl, substituted aryl, OH, NH₂,NO₂ and CN;

provided that:

(I) when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted (C₂-C₃₀)acyl,or substituted aryl(C₁-C₃₀)acyl, then R³ is H, (C₁-C₃₀)alkyl,(C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, aryl(C₁-C₃₀)alkyl, substituted(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted(C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl or substitutedaryl(C₁-C₃₀)alkyl;

(II) when R¹² is (C₁-C₄₀)acyl, aryl(C₁-C₄₀)acyl, substituted(C₁-C₄₀)acyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl, or—C(NH)—NH₂, then R¹³ is H or (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl,(C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl, aryl(C₁-C₄₀)alkyl, substituted(C₁-C₄₀)alkyl, substituted (C₁-C₄₀)heteroalkyl, substituted(C₂-C₄₀)alkenyl, substituted (C₂-C₄₀)alkynyl, or substitutedaryl(C₁-C₄₀)alkyl;

(III) at least one of A¹⁵, A¹⁶, A¹⁷, A¹⁸, A¹⁹ or A²⁰ of said ghrelinanalog is selected from the group consisting of Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) andHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); and

(IV) when any of the group consisting of A¹⁵, A¹⁶, A¹⁷, A¹⁹ and A²⁰ isHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O), then R¹² must be biotinyl;

or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of formula (I), termed Group 1 compounds,is where:

A¹ is Gly or Aib;

A² is Ser, Act, Aib, Ava or A5c;

A³ is Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶) orSer(C(O)—R⁴);

A⁴ is Phe;

A⁵ is Leu, Acc, Aib, Cha or hLeu;

A⁶ is Ser, Abu, Act, Aib or Thr;

A⁷ is Pro, Dhp, Dmt, 4Hyp, Ktp, Pip or Thz;

A⁸ is Glu or Aib;

A⁹ is His, Aib, Apc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Taz or 2-Thi;

A¹⁰ is Gln or Aib;

A¹¹ is Arg;

A¹² is Val or Acc;

A¹³ is Gln;

A¹⁴ is Gln;

A¹⁵ is Arg or Orn;

A¹¹ is Lys or Apc;

A¹⁷ is Glu;

A¹⁸ is Ser;

A¹⁹ is Lys;

A²⁰ is Lys;

A²¹ is Pro;

A²² is Pro;

A²³ is Ala;

A²⁴ is Lys;

A²⁵ is Leu;

A²⁶ is Gln;

A²⁷ is Pro; and

A²⁸ is Arg;

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of formula (I), termed Group 2compounds, is where:

each of R² and R³ is, independently for each occurrence thereof,selected from the group consisting of H, acyl, n-butyryl, isobutyryl andn-octanoyl;

R⁴ is heptyl;

R⁶ is hexyl;

R⁷ is hexyl;

R¹⁰ is octyl;

R¹¹ is heptyl; and

provided that when Acc is substituted for one of the naturally-occurringresidues, it is, independently for each occurrence, A3c, A4c, A5c orA6c;

or pharmaceutically acceptable salts thereof.

Another preferred group of compounds of the immediately preceding groupof compounds, termed Group 3 compounds, is where:

A³ is Asp(NH-hexyl), Asp(1-heptanol), Cys(S—(CH₂)₉CH₃),Dap(octanesulfonyl), Glu(NH-hexyl) or Glu(1-heptanol);

A⁵ is Leu;

A⁶ is Ser;

A⁷ is Pro, Dhp, 4-Hyp, Pip, Thz or Tic;

A⁹ is His, 3-Pal, 4-Pal, Taz or 2-Thi;

A¹² is Val;

A¹¹ is Arg, Glu(NH-hexyl) or Ser(n-octanoyl);

A¹⁶ is Lys, Glu(NH-hexyl) or Ser(n-octanoyl);

A¹⁷ is Glu, Lys(biotinyl), Asp(NH-hexyl), Asp(1-heptanol),Cys(S—(CH₂)₉CH₃), Dap(octanesulfonyl), Glu-(NH-hexyl), Glu(1-heptanol)or Ser(n-octanoyl);

A¹⁸ is Ser, Glu(NH-hexyl) or Ser(n-octanoyl);

A¹⁹ is Lys, Glu(NH-hexyl) or Ser(n-octanoyl);

A²⁰ is Lys, Glu(NH-hexyl) or Ser(n-octanoyl);

or a pharmaceutically acceptable salt thereof.

A more preferred group of compounds according to formula (I), termedGroup 4 compounds, includes compounds according to the formula:

(Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:1)(Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:2)(Glu(NH-hexyl)^(3,15)hGhrelin(1-28)-NH) ²; (SEQ ID NO:3)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:4)(Aib²,Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH²; (SEQ ID NO:5)(Aib2,Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:6)(Aib^(2,8),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:7)(Aib^(2,8),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:8)(Aib^(2,10),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:9)(Aib^(2,10),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:10)(Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:11)(Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:12)(Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:13)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:14)(Aib²,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:15)(Aib²,G1u(NH-hexyl)^(3,16))hGhre1in(1-28)-NH₂; (SEQ ID NO:16)(Aib^(2,8),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:17)(Aib²,8,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:18)(Aib²,10,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:19)(Aib²,10,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:20)(Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:21)(Glu(NH-hexyl)¹⁷)hGhre1in(1-28)-NH₂; (SEQ ID NO:22)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:23)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:24)(Dap(octanesu1fonyl)¹⁷hGhre1in(1-28)-NH₂; (SEQ ID NO:25)(Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:26)(Dap(octanesulfonyl)³,Glu(NH-hexyl)¹⁷)hGhrelin(1 -28)-NH₂; (SEQ IDNO:27) (Dap(octanesulfonyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:28) (Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:29) (Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:30)(Cys(S-(CH₂)₉CH_(3,17))hGhre1in(1-28)-NH₂; (SEQ ID NO:31)(Glu(NH-hexyl)³,Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:32)(Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:33)(Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:34)(Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:35)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,4-Hyp⁷,,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Tic⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Glu(NH-hexyl)^(3,17),Thz⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),4-HypDhGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:39)(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhre1in(1-28)-NH₂; (SEQ ID NO:40)(Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:43)(Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:44)(Aib⁸,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:45)(Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:47)(Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Aib^(1,2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:49)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:51)(A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:52)(Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:53)(Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:54)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:55)(Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:56)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:57)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:59)(Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:60)(Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:61)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:62)(Aib²,Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:63)(Aib²,Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:64)(Aib^(2,8),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:65)(Aib^(2,8),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:66)(Aib^(2,10),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:67)(Aib^(2,10),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:68)(Ser(n-octanoyl)19)hGhrelin(1-28)-NH₂; (SEQ ID NO:69)(Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:70)(Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:71)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:72)(Aib²,Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:73)(Aib²,Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:74)(Aib^(2,8),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:75)(Aib^(2,8),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:76)(Aib^(2,10),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:77)(Aib^(2,10),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:78)(Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:79)(Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:80)(Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:81)(Glu(NH-hexyl)³,Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:82)(Aib²,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:83)(Aib²,Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:84)(Aib^(2,8),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:85)(Aib^(2,8),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:86)(Aib^(2,10),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:87)(Aib^(2,10),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:88)(Ac-Gly¹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:89)(Ac-Gly¹,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:90)(Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:91)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:92) (Ac-Gly¹,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:93)(Ac-Gly¹,Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:94)(Ac-Gly¹,Dap(octanesulfonyl)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:95)(Ac-Gly¹,Dap(octanesulfonyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:96)(Ac-Gly¹,Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:97) (Ac-Gly¹,Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:98)(Ac-Gly¹,Cys(S-(CH₂)₉CH₃)¹⁷)hGhre1in(1-28)-NH₂; (SEQ ID NO:99)(Ac-Gly¹,Glu(NH-hexyl)³,Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:100) (Ac-Gly¹,Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)˜7)hGhrelin(1-28)-NH₂;(SEQ ID NO:101)(Ac-Glyl,Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:102) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁷)hGhre1in(1-28)-NH₂; (SEQ IDNO:103) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:104) (Ac-Gly¹,Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,4-Hyp⁷,,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:105) (Ac-Gly¹,Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:105) (Ac-Gly¹,Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:105) (Ac-Gly¹,Aib²,Tic⁷,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:105)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Thz⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Hyp⁷,)hGhrelin(1-28)-NH₂;(SEQ ID NO:106)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷hGhre1in(1-28)-NH₂; (SEQ IDNO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂; (SEQID NO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:106) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:107)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:108) (Ac-Gly¹,Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhre1in(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hre1in(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:110)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:110) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQID NO:110) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:110) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:111)(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:112) (Ac-Gly¹,Aib⁸,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:113) (Ac-Gly¹,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:115) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:117) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:118) (Ac-Gly¹,A5c²,Glu(NH-hexyl¹⁷)Ghre1in(1-28)-NH₂; (SEQ IDNO:119) (Ac-Gly¹,A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:120) (Ac-Gly¹,Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:121) (Ac-Gly¹,Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:122) (Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:123) (Ac-Gly¹,Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:124) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:125)(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)³,Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126) (Ac-Gly¹,Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:127) (Ac-Gly¹,Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:128)(Ac-Gly¹,Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:129)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:130) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:131) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ IDNO:132) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:133) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQID NO:134) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQID NO:135) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂;(SEQ ID NO:136) (Ac-Gly¹,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:137) (Ac-Gly¹,Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:138)(Ac-Gly¹,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:139)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:140) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:141) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ IDNO:142) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:143) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQID NO:144) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQID NO:145) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂;(SEQ ID NO:146) (Ac-Gly¹,Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:147) (Ac-Gly¹,Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:148)(Ac-Gly¹,Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:149)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:150) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:151) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ IDNO:152) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:153) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQID NO:154) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQID NO:155) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂;(SEQ ID NO:156) (Ac-Gly¹,Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:157) (Ac-Gly¹,Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:158)(Ac-Gly¹,Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:159)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:160) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:161) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ IDNO:162) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:163) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQID NO:164) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQID NO:165) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂;(SEQ ID NO:166) (Ac-Gly¹,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:167) (Ac-Gly¹,Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:168)(Ac-Gly¹,Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:169)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:170) (Ac-Gly¹,Aib²,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:171) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ IDNO:172) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:173) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQID NO:174) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQID NO:175) and(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ IDNO:176)or pharmaceutically acceptable salts thereof.

A yet more preferred group of compounds according to formula (I), termedGroup 5 compounds, includes compounds according to the formula:

(Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:21)(Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:22)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:23)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:24)(Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:25)(Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:26)(Dap(octanesulfonyl)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:27)(Dap(octanesulfonyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:28) (Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:29) (Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:30)(Cys(S-(CH₂)₉CH₃)^(3,17))hGhre1in(1-28)-NH₂; (SEQ ID NO:31)(Glu(NH-hexyl)³,Cys(S-(CH₂)₉CH₃)¹⁷)hGhreliri(1-28)-NH₂; (SEQ ID NO:32)(Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:33)(Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:34)(Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:35)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,4-Hyp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Tic⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Glu(NH-hexyl)^(3,17),Thz⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),4-Hyp⁷,)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:39)(Aib^(2.8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:43)(Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:44)(Aib⁸,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:45)(Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:47)(Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)3.17,3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Aib^(1,2,10),Ghi(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:49)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:51)(A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:52)(Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:53)(Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:54)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:55)(Asp(NH-hexyl)^(3,17)))hGhrelin(1-28)-NH₂; (SEQ ID NO:56)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:57)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ac-Gly¹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:89)(Ac-Gly¹,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:90)(Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:91)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:92) (Ac-Gly¹,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:93)(Ac-Gly¹,Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:94)(Ac-Gly¹,Dap(octanesulfonyl)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:95)(Ac-Gly¹,Dap(octanesulfonyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:96)(Ac-Gly¹,Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:97) (Ac-Gly¹,Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:98)(Ac-Gly¹,Cys(S-(CH₂)₉CH₃)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:99)(Ac-Gly¹,Glu(NH-hexyl)³,Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:100) (Ac-Gly¹,Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:101)(Ac-Gly¹,Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:102) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:103) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:104) (Ac-Gly¹,Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,4-Hyp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,Tic⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Thz⁷)hGhrelin(1-28)-NH₂; (SEQID NO:106)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Hyp⁷,)hGhrelin(1-28)-NH₂; (SEQ IDNO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷)hGhrelin(1-28)-NH₂; (SEQID NO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:106)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:106) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:107) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQID NO:108) (Ac-Gly¹,Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:109) (Ac-Gly¹,Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:109) (Ac-Gly¹,Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:109) (Ac-Gly¹,Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:109) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:110)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:110) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQID NO:110) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:110) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:111)(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:112) (Ac-Gly¹,Aib⁸,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:113) (Ac-Gly¹,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:115) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:117) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:118) (Ac-Gly¹,A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:119) (Ac-Gly¹,A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQID NO:120) (Ac-Gly¹,Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:121) (Ac-Gly¹,Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:122) (Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:123) (Ac-Gly¹,Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:124) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:125) and(Ac-Gly¹,Aib²,10,Glu(NH-hexyl)^(3,Lys)(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126)or pharmaceutically acceptable salts thereof.

A still more preferred group of compounds according to formula (I),termed Group 6 compounds, includes compounds according to the formula:

(Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:21)(Glu(NH-hexyl)¹⁷hGhrelin(1-28)-NH₂; (SEQ ID NO:22)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:23)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:24)(Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:35)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:39)(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:43)(Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:44)(Aib^(1,2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:49)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:51)(A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:52)(Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:53)(Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:54)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:55)(Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:56)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:57)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ac-Gly¹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:89)(Ac-Gly¹,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:90)(Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:91)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:92) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:103)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:104)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:107)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:108) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:111) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:112) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:117)(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:118) (Ac-Gly¹,A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:119) (Ac-Gly¹,A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:120) (Ac-Gly¹,Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:121) (Ac-Gly¹,Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:122) (Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:123) (Ac-Gly¹,Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:124) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:125) and(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)³,Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126)or pharmaceutically acceptable salts thereof.

A still more preferred group of compounds according to formula (I),termed Group 7 compounds, includes compounds according to the formula:

(Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:21)(Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:22)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:23)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:24)(Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:35)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:39)(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:43)(Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:44)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:51)(A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:52)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ac-Gly¹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:89)(Ac-Gly¹,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:90)(Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:91)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:92) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:103)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:104)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:107)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:108) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:111) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:112) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:117)(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:118) (Ac-Gly¹,A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:119) (Ac-Gly¹,A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:120) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:125) or(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,Lys)(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126)or a pharmaceutically acceptable salt thereof.

A preferred group of compounds according to formula (I), termed Group 8compounds, includes compounds according to the formula:

A¹ is Ac-Gly, Ac-Aib or Aib;

A² is Aib;

A³ is Glu(NH-hexyl);

A⁸ is Aib;

A¹⁰ is Aib; and

A¹⁷ is Glu(NH-hexyl) or Lys(biotinyl);

or pharmaceutically acceptable salts thereof.

A more preferred group of immediately preceding compounds according toformula (I), termed Group 9 compounds, includes compounds wherein R² andR³ is, independently for each occurrence thereof, selected from thegroup consisting of H, acyl, n-butyryl, isobutyryl and n-octanoyl and R¹is NH₂;

or pharmaceutically acceptable salts thereof.

An even more preferred group of immediately preceding compoundsaccording to formula (I), termed Group 10 compounds, includes compoundsaccording to the formula:

(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:104)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:108) (Ac-Gly¹,Aib^(2,10,Glu(NH-hexyl)) ^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:112)(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:118) and(Ac-Gly¹,Aib²,101Glu(NH-hexyl)^(3,Lys)(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126)or pharmaceutically acceptable salts thereof.

And even more preferred to the immediately foregoing group of compoundsaccording to formula (I), termed Group 11 compounds, includes compoundsaccording to the formula:

(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58) and(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:118)or pharmaceutically acceptable salts thereof.

And even more preferred to the immediately foregoing group of compoundsaccording to formula (I), termed a Group 12 compound, includes acompound of the formula:

(SEQ ID NO:58) (Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;or a pharmaceutically acceptable salt thereof.

A second aspect of the present invention describes a ghrelin analogaccording to formula (II):

(R²R³)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵- A²⁶-A²⁷-A²⁸-R¹ (II)wherein:

A¹ is Gly, Acc, Aib, Ala, β-Ala or Gly(myristyl);

A² is Ser, Abu, Acc, Act, Aib, Ala, Ava, Thr or Val;

A³ is Ser, Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O);

A⁴ is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal,hPhe, (X¹,X²,X³,X⁴,X⁵)Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr;

A⁵ is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle orVal;

A⁶ is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;

A⁷ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;

A⁸ is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O);

A⁹ is His, Acc, Aib, Apc, 2-Fua, 2-Pal, 3-Pal, 4-Pal,(X¹,X²,X³,X⁴,X⁵—)Phe, Taz, 2-Thi or 3-Thi;

A¹⁰ is Gln, Acc, Aib, Asn, Asp or Glu;

A¹¹ is Arg, Apc, hArg, Dab, Dap, Lys, Orn orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O);

A¹² is Val, Abu, Acc, Aib, Ala, Cha, Nva, Gly, Ile, Leu, Nle or Tle;

A¹³ is Gln, Acc, Aib, Asn, Asp or Glu;

A¹⁴ is Gln, Acc, Aib, Asn, Asp or Glu;

A¹⁵ is Arg, Acc, Aib, Apc, hArg, Dab, Dap, Lys, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R⁷),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O);

A¹⁶ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷, Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A¹⁷ is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Lys(biotinyl), Lys(myristyl),Ser(C(O)—R⁴), Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A¹⁸ is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val, Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A¹⁹ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A²⁰ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A²¹ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic ordeleted;

A²² is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic ordeleted;

A²³ is Abu, Acc, Act, Aib, Ala, Apc, Gly, Nva, Val or deleted;

A²⁴ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn,HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

A²⁵ is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Valor deleted;

A²⁶ is Gln, Aib, Asn, Asp, Glu or deleted;

A²⁷ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic ordeleted;

A²⁵ is Acc, Aib, Apc, Arg, hArg, Dab, Dap, Lys, Orn,HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;

R¹ is —OH, —NH₂, —(C₁-C₃₀)alkoxy or NH—X⁶—CH₂-Z⁰, wherein X⁶ is a(C₁-C₁₂)alkyl or (C₂-C₁₂)alkenyl and Z⁰ is —H, —OH, —CO₂H or —C(O)—NH₂;

each of R² and R³ is, independently for each occurrence thereof,selected from the group consisting of H, (C₁-C₃₀)alkyl,(C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl,aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)alkyl,substituted (C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)acyl, substituted(C₂-C₃₀)alkenyl, substituted aryl(C₁-C₃₀)alkyl, substituted(C₂-C₃₀)alkynyl and substituted aryl(C₁-C₃₀)acyl or may be deleted;

each of R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is,independently for each occurrence thereof, selected from the groupconsisting of (C₁-C₄₀)alkyl, (C₂-C₄₀)alkenyl, substituted (C₁-C₄₀)alkyl, substituted (C₂-C₄₀) alkenyl, alkylaryl, substituted alkylaryl,aryl and substituted aryl;

each of R¹² and R¹³ is, independently for each occurrence, selected fromthe group consisting of H, (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl,(C₁-C₄₀)acyl, (C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl, aryl(C₁-C₄₀)alkyl,aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)alkyl, substituted(C₁-C₄₀)heteroalkyl, substituted (C₁-C₄₀)acyl, substituted(C₂-C₄₀)alkenyl, substituted (C₂-C₄₀)alkynyl, substitutedaryl(C₁-C₄₀)alkyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl,—C(NH)—NH₂ and biotinyl;

n is, independently for each occurrence thereof, 1, 2, 3, 4 or 5;

each of X¹, X², X³, X⁴, and X¹ is, independently for each occurrencethereof, selected from the group consisting of H, F, Cl, Br, I,(C₁₋₁₀)alkyl, substituted (C₁₋₁₀)alkyl, aryl, substituted aryl, OH, NH₂,NO₂ and CN;

provided that:

(I) when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted (C₂-C₃₀)acyl,or substituted aryl(C₁-C₃₀)acyl, then R³ is H, (C₁-C₃₀)alkyl,(C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, aryl(C₁-C₃₀)alkyl, substituted(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted(C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl or substitutedaryl(C₁-C₃₀)alkyl;

(II) when R¹² is (C₁-C₄₀)acyl, aryl(C₁-C₄₀)acyl, substituted(C₁-C₄₀)acyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl, or—C(NH)—NH₂, then R¹³ is H or (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl,(C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl, aryl(C₁-C₄₀)alkyl, substituted(C₁-C₄₀)alkyl, substituted (C₁-C₄₀)heteroalkyl, substituted(C₂-C₄₀)alkenyl, substituted (C₂-C₄₀)alkynyl, or substitutedaryl(C₁-C₄₀)alkyl;

(III) at least one of A¹⁵, A¹⁶, A¹⁷, A¹⁸, A¹⁹ or A²⁰ of said ghrelinanalog is selected from the group consisting of Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); and

(IV) when any of the group consisting of A¹⁵, A¹⁶, A¹⁷, A¹⁹ and A²⁰ isHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O), then R¹² must be biotinyl;

or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of formula (II), termed Group 13compounds, is where:

A¹ is Gly or Gly(myristyl;

A² is Ser or Aib; and

A¹ is Ser(n-octanoyl) or Lys(myristyl);

or a pharmaceutically acceptable salt thereof.

Yet another preferred group of compounds of formula (II), termed Group14 compounds, is where:

A¹⁷ is Lys(myristyl).

A more preferred group of compounds of the preceding group of compounds,termed Group 15 compounds, is where:

R² selected from the group consisting of H, acyl, n-butyryl, isobutyryl,n-octanoyl and myristyl;

R³ is deleted;

R⁴ is heptyl;

R⁶ is hexyl;

R⁷ is hexyl;

R¹⁰ is octyl; and

R¹¹ is heptyl;

provided that when Acc is substituted for any one of thenaturally-occurring residues of the sequence, it is, independently foreach occurrence, selected from the group consisting of A3c, A4c, A5c andA6c;

or pharmaceutically acceptable salts thereof.

An even more preferred group of compounds according to formula (II),termed Group 16 compounds, includes compounds according to the formula:

(Aib², Lys(myristyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:177) and

(Gly(myristyl)¹, Aib², Lys(myristyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:178)

or pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formulae (I)or (II), more preferably a compound according to one or more of Group 1,Group 2, Group 3, Group 4, Group 5, Group 6, Group 7, Group 8, Group 9,Group 10, Group 11, Group 12, Group 13, Group 14, Group 15 and/or Group16 as defined hereinabove, or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier or diluent.

Ghrelin analogs described herein are active at the GHS receptor. Theanalogs can bind to the receptor and stimulate or inhibit the receptoractivity. Ghrelin analogs have a variety of different uses including,but not limited to, being employed as a research tool or as atherapeutic agent.

Research tool applications generally involve the use of a ghrelin analogand the presence of a GHS receptor or fragment thereof. The GHS receptorcan be present in different environments such as a mammalian subject, awhole cell or a membrane fragment. Examples of research toolapplications include, but are not limited to, screening for compoundsactive at the GHS receptor, determining the presence of the GHS receptorin a sample or preparation and examining the role or effect of ghrelin.

Ghrelin analogs can be used to screen for both ghrelin agonists andghrelin antagonists. Screening for ghrelin agonists can be performed,for example, by using a ghrelin analog in a competition experiment withtest compounds. Screening for ghrelin antagonists can be performed, forexample, by using a ghrelin analog to produce GHS receptor activity andthen measuring the ability of a compound to alter GHS receptor activity.

Another aspect of the present invention features a method of screeningfor a compound able to bind to a GHS receptor. The method comprises thestep of measuring the ability of a compound to affect binding of aghrelin analog to the receptor, a fragment of the receptor comprising aghrelin binding site, a polypeptide comprising the fragment or aderivative of the polypeptide. Compounds useful for screening includecompounds encompassed by formulae (I) or (II), more preferably acompound according to one or more of Group 1, Group 2, Group 3, Group 4,Group 5, Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group12, Group 13, Group 14, Group 15 and/or Group 16, as definedhereinabove, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or diluent.

Another aspect of the present invention features a method for achievinga beneficial effect in a subject comprising administering to saidsubject an effective amount of one or more of a compound according toformulae (I) or (II), more preferably a compound according to one ormore of Group 1, Group 2, Group 3, Group 4, Group 5, Group 6, Group 7,Group 8, Group 9, Group 10, Group 11, Group 12, Group 13, Group 14,Group 15 and/or Group 16, or pharmaceutically acceptable salts thereof,wherein said effective amount is effective for producing a beneficialeffect in helping to treat (e.g., cure or reduce the severity) or toprevent (e.g., reduce the likelihood of onset or severity) a disease ordisorder.

Ghrelin induces GH release from primary-culture pituitary cells in adose-dependent manner without stimulating the release of the otherpituitary hormones. Injected intravenously into anaesthetized rats,ghrelin stimulated the pulsatile release of GH (Kojima, M. et al.,Nature, (1999), 402(6762):656-60), thus another aspect of the presentinvention features a method for stimulating GH secretion in a subject inneed thereof, comprising administering an effective amount of one ormore of a compound according to formulae (I) or (II), more preferably acompound according to one or more of Group 1, Group 2, Group 3, Group 4,Group 5, Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group12, Group 13, Group 14, Group 15 and/or Group 16, or pharmaceuticallyacceptable salts thereof, wherein said effective amount is at least anamount sufficient to produce a detectable increase in GH secretion and,preferably, is an amount sufficient to achieve a beneficial effect in apatient.

A preferred method of the immediately preceding method is wherein saidstimulation of GH secretion is indicated for treating a GH deficientstate, increasing muscle mass and/or bone density, overcoming sexualdysfunction, gaining body weight and/or maintaining an ideal bodyweight, maintaining and/or regaining physical functioning and/orincreasing appetite.

A preferred method of the immediately preceding method is where saidweight gain or maintenance thereof or appetite increase is indicated ina patient having a disease or disorder or under going a treatmentaccompanied by weight loss.

A preferred method of the immediately preceding method is where saiddisease accompanied by weight loss is associated with the onset ofcachexia which include, but are not limited to, anorexia, bulimia,cancer, AIDS and chronic obstructive pulmonary disease (COPD). Anotheraspect of the immediately preceding method is wherein said weight lossis due to the onset of wasting syndrome, particularly in the frail orelderly. A further preferred method of the preceding method is tofacilitate weight gain after an unexplained weight loss in an otherwisehealthy elderly patient or to prevent, treat or alleviate the onset ofAlzheimer's disease. In yet another preferred method of said immediatelypreceding method is where said treatments accompanied by weight lossinclude chemotherapy, radiation therapy, temporary immobilization,permanent immobilization and dialysis.

Another preferred method of the immediately preceding method is wheresaid weight gain or maintenance thereof and/or appetite increase isindicated in an otherwise healthy patient not suffering from aparticular disease or disorder or undergoing one of the aforementionedtreatments.

Ghrelin analogs described herein may also antagonize the effects ofghrelin in vitro and in vivo, thus another aspect of the presentinvention features a method for suppressing GH secretion in a subject inneed thereof by administering an effective amount of one or more of acompound according to formulae (I) or (II), more preferably a compoundaccording to one or more of Group 1, Group 2, Group 3, Group 4, Group 5,Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group 12, Group13, Group 14, Group 15 and/or Group 16, or pharmaceutically acceptablesalts thereof, wherein said effective amount is at least an amountsufficient to produce a detectable decrease in GH secretion and,preferably, is an amount sufficient to achieve a beneficial effect in apatient.

A preferred method of the immediately preceding method is wherein saidsuppression of GH secretion is indicated for treating excessive GHsecretion, losing weight, decreasing appetite, maintaining an idealweight, overcoming obesity, managing diabetes and its complications suchas retinopathy and/or treating a cardiovascular disorder.

The immediately preceding method is preferred when excessive weight gainis a contributing factor of a disease or condition including, but notlimited to, hypertension, diabetes, dyslipidemia, cardiovasculardisease, gall stones, osteoarthritis and certain cancers, particularlywherein said weight loss reduces the likelihood of such diseases orcomprises at least part of a treatment for such diseases or conditions.

Ghrelin agonists or analogs according to formulae (I) or (II), morepreferably a compound according to one or more of Group 1, Group 2,Group 3, Group 4, Group 5, Group 6, Group 7, Group 8, Group 9, Group 10,Group 11, Group 12, Group 13, Group 14, Group 15 and/or Group 16, can beused to achieve a beneficial effect in a subject such as one or more ofthe following: treating a GH deficient state, increasing muscle massand/or bone density, overcoming sexual dysfunction, facilitating aweight gain, maintaining an ideal weight, recovering and/or restoringnormal physical functions and/or increasing appetite. Facilitating aweight gain, maintaining body weight and/or increasing appetite areparticularly useful for treating a patient suffering from cachexia orwasting syndrome associated with a disease or disorder or undergoing amedical or therapeutic regimen which is normally accompanied by weightloss. Examples of diseases or disorders accompanied by weight loss dueto cachexia include anorexia, bulimia, cancer and AIDS. Gaining bodyweight, maintaining and ideal body weight or increasing appetite areespecially beneficial to patients suffering from wasting syndrome,especially the frail and elderly. Examples of treatments accompanied byweight loss include chemotherapy, radiation therapy, temporary orpermanent immobilization and/or dialysis.

Ghrelin agonists or analogs according to formulae (I) or (II), morepreferably a compound according to one or more of Group 1, Group 2,Group 3, Group 4, Group 5, Group 6, Group 7, Group 8, Group 9, Group 10,Group 11, Group 12, Group 13, Group 14, Group 15 and/or Group 16, havebeen successful in treating a subject suffering from post-operativeileus or chronic obstructive pulmonary disease.

In addition, ghrelin has been effective in treating inflammation in amammalian subject. Thus, in one aspect the invention, the inventionprovides a method for treating inflammation in a subject in need thereofby administering an effective amount of one or more of a compoundaccording to formulae (I) or (II), more preferably a compound accordingto one or more of Group 1, Group 2, Group 3, Group 4, Group 5, Group 6,Group 7, Group 8, Group 9, Group 10, Group 11, Group 12, Group 13, Group14, Group 15 and/or Group 16, or pharmaceutically acceptable saltsthereof, wherein said effective amount is at least an amount sufficientto produce a detectable decrease in the inflammation and, preferably, isan amount sufficient to achieve a beneficial effect in a patient.

In one aspect of the immediately foregoing method, the inflammation isassociated with a viral, bacterial, parasitic or fungal infection. Inone aspect of the foregoing method, the inflammation is associated witha viral infection. Viral infections treatable with ghrelin, ghrelinanalogs and/or ghrelin agonists include, but are not limited to, Herpessimplex virus type-1, Herpes simplex virus type-2, Cytomegalovirus,Epstein-Barr virus, Varicella-zoster virus, Human herpesvirus 6, Humanherpesvirus 7, Human herpesvirus 8, Variola virus, Vesicular stomatitisvirus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus,Hepatitis D virus, Hepatitis E virus, Rhinovirus, Coronavirus, Influenzavirus A, Influenza virus B, Measles virus, Polyomavirus, HumanPapilomavirus, Respiratory syncytial virus, Adenovirus, Coxsackie virus,Dengue virus, Mumps virus, Poliovirus, Rabies virus, Rous sarcoma virus,Yellow fever virus, Ebola virus, Marburg virus, Lassa fever virus,Eastern Equine Encephalitis virus, Japanese Encephalitis virus, St.Louis Encephalitis virus, Murray Valley fever virus, West Nile virus,Rift Valley fever virus, Rotavirus A, Rotavirus B, Rotavirus C, Sindbisvirus, Simian Immunodeficiency virus, Human T-cell Leukemia virustype-1,Hantavirus, Rubella virus, Simian Immunodeficiency virus, HumanImmunodeficiency virus type-1 and/or Human Immunodeficiency virustype-2.

In another aspect of the foregoing method, the inflammation isassociated with a bacterial infection. Bacterial infections that causeinflammation that are treatable with ghrelin, one or more ghrelin analogor a ghrelin agonist include, but are not limited to, M. tuberculosis, Mbovis, M. bovis strain BCG, BCG substrains, M. avium, M. intracellulare,M. africanum, M. kansasii, M. marinum, M. ulcerans, M. avium subspeciesparatuberculosis, Nocardia asteroides, other Nocardia species,Legionella pneumophila, other Legionella species, Salmonella typhi,other Salmonella species, Shigella species, Yersinia pestis, Pasteurellahaemolytica, Pasteurella multocida, other Pasteurella species,Actinobacillus pleuropneumoniae, Listeria monocytogenes, Listeriaivanovii, Brucella abortus, other Brucella species, Cowdria ruminantium,Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia psittaci,Coxiella burnetti, other Rickettsia species, Ehrlichia species,Staphylococcus aureus, Staphylococcus epidermidis, Streptococcuspyogenes, Streptococcus agalactiae, Bacillus anthracis, Escherichiacoli, Vibrio cholerae, Campylobacter species, Neiserria meningitidis,Neiserria gonorrhea, Pseudomonas aeruginosa, other Pseudomonas species,Haemophilus influenzae, Haemophilus ducreyi, other Hemophilus species,Clostridium tetani, other Clostridium species, Yersinia enteroliticaand/or other Yersinia species.

In another aspect of the foregoing method, the inflammation isassociated with a parasitic or fungal infection. Parasitic infectionstreatable with ghrelin, one or more ghrelin analog or a ghrelin agonistinclude, but are not limited to, Toxoplasma gondii, Plasmodium,Trypanosoma brucei, Trypanosoma cruzi, Leishmania, Schistosoma and/orEntamoeba histolytica. Fungal infections treatable with ghrelin, ghrelinanalogs or ghrelin agonists include, but are not limited to, Candidaalbicans, Cryptococcus neoformans, Histoplama capsulatum, Aspergillusfumigatus, Coccidiodes immitis, Paracoccidiodes brasiliensis,Blastomyces dermitidis, Pneomocystis carnii, Penicillium marneffi and/orAlternaria alternata.

In another aspect of the invention, inflammation caused by livertoxicity or transplant rejection is also treatable by administering aneffective amount of one or more of a compound according to formulae (I)or (II), more preferably a compound according to one or more of Group 1,Group 2, Group 3, Group 4, Group 5, Group 6, Group 7, Group 8, Group 9,Group 10, Group 11, Group 12, Group 13, Group 14, Group 15 and/or Group16, or pharmaceutically acceptable salts thereof, wherein said effectiveamount is at least an amount sufficient to produce a detectable decreasein the inflammation and, preferably, is an amount sufficient to achievea beneficial effect in a patient. The liver toxicity may be associatedwith cancer therapy. In some instances, the cancer therapy, such aschemotherapy, may bring about liver toxicity. Liver toxicity broughtabout by both chemotherapy and apoptosis may be treatable byadministration of ghrelin, ghrelin agonists and/or ghrelin antagonists.

In yet a further aspect of the invention, inflammation associated withcancers is also treatable by administering an effective amount of one ormore of a compound according to formulae (I) or (II), more preferably acompound according to one or more of Group 1, Group 2, Group 3, Group 4,Group 5, Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group12, Group 13, Group 14, Group 15 and/or Group 16, or pharmaceuticallyacceptable salts thereof, wherein said effective amount is at least anamount sufficient to produce a detectable decrease in the inflammationand, preferably, is an amount sufficient to achieve a beneficial effectin a patient. Such cancers include, but are not limited to, lymphoma,leukemia, mycosis fungoide, carcinoma, adenocarcinoma, sarcoma, glioma,blastoma, neuroblastoma, plasmacytoma, histiocytoma, melanoma, adenoma,hypoxic tumor, myeloma, AIDS-related lymphoma or AIDS-related sarcoma,metastatic cancer, bladder cancer, brain cancer, nervous system cancer,glioblastoma, ovarian cancer, skin cancer, liver cancer, squamous cellcarcinomas of the mouth, throat, larynx, and lung, colon cancer,cervical cancer, breast cancer, epithelial cancer, renal cancer,genitourinary cancer, pulmonary cancer, esophageal carcinoma, head andneck carcinoma, hematopoietic cancer, testicular cancer, colo-rectalcancer, prostatic cancer and/or pancreatic cancer.

In yet a further aspect of the invention, inflammatory diseases are alsotreatable by administering an effective amount of one or more of acompound according to formulae (I) or (II), more preferably a compoundaccording to one or more of Group 1, Group 2, Group 3, Group 4, Group 5,Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group 12, Group13, Group 14, Group 15 and/or Group 16, or pharmaceutically acceptablesalts thereof, wherein said effective amount is at least an amountsufficient to produce a detectable decrease in the inflammation and,preferably, is an amount sufficient to achieve a beneficial effect in apatient. Inflammatory diseases treatable by ghrelin, one or more ghrelinagonists and/or ghrelin antagonists of the invention include, but arenot limited to, asthma, reactive arthritis, hepatitis, spondyarthritis,Sjogren's syndrome, Alzheimer's disease, and atopic dermatitis orinflammatory diseases associated with an autoimmune disease such assystemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis,insulin dependent diabetes mellitus, multiple sclerosis, musculardystrophy, experimental allergic encephalomyelitis, psoriasis, Crohn'sdisease, inflammatory bowel disease, ulcerative colitis, Addison'sdisease, alopecia aretea, celiac disease, thyroid disease and/orscleroderma. Inflammation as a result of a burn may also benefit fromtreatment with ghrelin, one or more ghrelin agonist and/or one or moreghrelin antagonist. Inflammation of the lung may also be treated withghrelin, one or more ghrelin agonist and/or one or more ghrelinantagonist. Inflammation may also cause a subject to lose appetite,particularly when the inflammation is low grade and/or in an agingsubject.

Ghrelin antagonists can also be used to achieve a beneficial effect in apatient. For example, a ghrelin antagonist can be used to facilitateweight loss and/or a decrease in appetite, maintain an ideal bodyweight, reverse obesity, treat diabetes, and complications thereof suchas retinopathy and/or improve cardiovascular disorders. Excessive weightis a contributing factor to different diseases including, but notlimited to, hypertension, diabetes, dyslipidemia, cardiovasculardisease, gall stone formation, osteoarthritis, Prader-Willi syndromeand/or certain forms of cancers. Loss of weight has been proven toreduce the likelihood of such diseases when part of the prescribedtreatment for such diseases.

Other features and advantages of the present invention are apparent fromthe additional descriptions provided herein, including the differentexamples. The provided examples illustrate different components andmethodology useful in practicing the present invention. The examples donot limit the claimed invention. Based on the present disclosure theskilled artisan can identify and employ other components and methodologyuseful for practicing the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention features ghrelin analogs active at the GHSreceptor. Human ghrelin is a 28 amino acid modified peptide wherein aserine hydroxyl group is esterified by n-octanoic acid. (Kojima, M. etal., Nature, (1999), 402(6762):656-60 and Kojima, M. (Abstract), ThirdInternational Symposium on Growth Hormone Secretagogues, Keystone,Colo., USA 2000, February 17-19).

As detailed above, the analogs of the instant invention are useful forthe treatment of a wide variety of ailments in a subject. A “subject”,as used herein and throughout this application, refers to a mammalian ornon-mammalian animal including, for example and without limitation, ahuman, a rat, a mouse or farm animal. Reference to a subject does notnecessarily indicate the presence of a disease or disorder. The term“subject” includes, for example, a mammalian or non-mammalian animalbeing dosed with a ghrelin analog as part of an experiment, a mammalianor non-mammalian animal being treated to help alleviate a disease ordisorder, and a mammalian or non-mammalian animal being treatedprophylactically to retard or prevent the onset of a disease ordisorder.

A “therapeutically acceptable amount” of a compound or composition ofthe invention, regardless of the formulation or route of administration,is that amount which elicits a desired biological response in a subject.The biological effect of the therapeutic amount may occur at and bemeasured at many levels in an organism. For example, the biologicaleffect of the therapeutic amount may occur at and be measured at thecellular level by measuring the response at a receptor which bindsghrelin and/or a ghrelin analog, or the biological effect of thetherapeutic amount may occur at and be measured at the system level,such as effecting an increase/decrease in the levels of circulatinggrowth hormone. The biological effect of the therapeutic amount mayoccur at and be measured at the organism level, such as the alleviationof a symptom(s) or progression of a disease or condition in a subject. Atherapeutically acceptable amount of a compound or composition of theinvention, regardless of the formulation or route of administration, mayresult in one or more biological responses in a subject. In the eventthat the compound or composition of the invention is subject to testingin an in vitro system, a therapeutically acceptable amount of thecompound or composition may be viewed as that amount which gives ameasurable response in the in vitro system of choice.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Also, all publications, patentapplications, patents and other references mentioned herein areincorporated by reference.

Certain amino acids present in compounds of the invention can be and arerepresented herein as follows:

Nomenclature and Abbreviations Symbol Meaning Abu α-aminobutyric acidAcc 1-amino-1-cyclo(C₃-C₉)alkyl carboxylic acid A3c1-amino-1-cyclopropanecarboxylic acid A4c1-amino-1-cyclobutanecarboxylic acid A5c1-amino-1-cyclopentanecarboxylic acid A6c1-amino-1-cyclohexanecarboxylic acid

Act denotes the structure Aib α-aminoisobutyric acid Aic2-aminoindan-2-carboxylic acid Ala or A alanine β-Ala beta-alanine

Apc denotes the structure: Arg or R arginine hArg homoarginine Asn or Nasparagine Asp or D aspartic acid Ava 5-amino-n-valeric acid Chaβ-cyclohexylalanine Cys or C cysteine hCys L-homocysteine Dab2,4-diaminobutyric acid Dap 2,3-diaminopropionic acid Dhp3,4-dehydroproline Dmt 5,5-dimethylthiazolidine-4-carboxylic acid 2-Fuaβ-(2-furyl)-alanine Gln or Q glutamine Glu or E glutamic acid Gly or Gglycine His or H histidine 3-Hyp trans-3-hydroxy-L-proline, i.e., (2S,3S)-3- hydroxypyrrolidine-2-carboxylic acid 4-Hyp 4-hydroxyproline,i.e., (2S, 4R)-4-hydroxypyrrolidine-2- carboxylic acid Ile or Iisoleucine Inc indoline-2-carboxylic acid Inp isonipecotic acid Ktp4-ketoproline Leu or L leucine hLeu homoleucine Lys or K lysine Met or Mmethionine 1-Nal β-(1-naphthyl)-L-alanine 2-Nal β-(2-naphthyl)-L-alanineNle norleucine Nva norvaline Oic octahydroindole-2-carboxylic acid Ornornithine 2-Pal β-(2-pyridinyl)alanine 3-Pal β-(3-pyridinyl)alanine4-Pal β-(4-pyridinyl)alanine Phe or F phenylalanine hPhehomophenylalanine Pip pipecolic acid Pro or P proline Ser or S serine

Taz β-(4-thiazolyl)alanine, i.e., 2-Thi β-(2-thienyl)alanine 3-Thiβ-(3-thienyl)alanine Thp 4-amino-4-carboxytetrahydropyran Thr or Tthreonine Thz thiazolidine-4-carboxylic acid Tic1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Tie tert-leucine Trp orW tryptophan Tyr or Y tyrosine Val or V valine

Where the amino acid has isomeric forms, it is the L form of the aminoacid that is represented unless otherwise explicitly indicated.

The nomenclature used to define the peptides is that typically used inthe art wherein the amino group at the N-terminus appears to the leftand the carboxyl group at the C-terminus appears to the right, i.e.,stand for the structure of —NH—CI(R′)—CO—, wherein R and R′ each is,independently, hydrogen or the side chain of an amino acid (e.g., R═CH₃and R′═H for Ala), or R and R′ may be joined to form a ring system. Forthe N-terminal amino acid, the abbreviation stands for the structure of:

A peptide of this invention is also denoted herein by another format,e.g., (Aib²)hGhrelin(1-28)-NH₂, with the substituted amino acid(s) fromthe natural sequence placed between the first set of parentheses (e.g.,Aib² for Ser² in hGhrelin). The numbers between the second set ofparentheses refer to the number of amino acids present in the peptide(e.g., hGhrelin(1-18) refers to amino acids 1 through 18 of the peptidesequence for human Ghrelin). The designation “NH₂” in e.g.,(Aib²)hGhrelin(1-28)-NH₂, indicates that the C-terminus of the peptideis amidated. (Aib²)hGhrelin(1-28), or, alternatively,(Aib²)hGhrelin(1-28)-OH indicates that the C-terminus is the free acid.A lower case letter is inserted before “Ghrelin” to indicate its sourceor origin, i.e. “h” indicates that the ghrelin is a homologue of theform of ghrelin found in homo sapiens.

Unless otherwise stated, those amino acids with a chiral center areprovided in the L-enantiomer. Reference to “a derivative thereof” refersto a modified amino acid such as the corresponding D-amino acid,N-alkyl-amino acid, β-amino acid or labeled amino acid.

As used herein, Acc encompasses an amino acid selected from the group of1-amino-1-cyclopropanecarboxylic acid (A3c);1-amino-1-cyclobutanecarboxylic acid (A4c);1-amino-1-cyclopentanecarboxylic acid (A5c);1-amino-1-cyclohexanecarboxylic acid (A6c);1-amino-1-cycloheptanecarboxylic acid (A7c);1-amino-1-cyclooctanecarboxylic acid (A8c); and1-amino-1-cyclononanecarboxylic acid (A9c).

“Acyl” refers to R″—C(O)—, where R″ is H, alkyl, substituted alkyl,heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl,aryl, alkylaryl or substituted alkylaryl.

“Alkyl” refers to a hydrocarbon group containing one or more carbonatoms, where multiple carbon atoms if present are joined by singlebonds. The alkyl hydrocarbon group may be straight-chain or contain oneor more branches or cyclic groups.

“Substituted alkyl” refers to an alkyl wherein one or more hydrogenatoms of the hydrocarbon group are replaced with one or moresubstituents selected from the group consisting of halogen (i.e.,fluorine, chlorine, bromine and iodine), —OH, —CN, —SH, —NH₂, —NHCH₃,—NO₂, —C₁₋₂₀ alkyl substituted with 1 to 6 halogens, —CF₃, —OCH₃, —OCF₃and —(CH₂)₀₋₂₀—COOH. In different embodiments 1, 2, 3 or 4 substituentsare present. The presence of —(CH₂)₀₋₂₀—COOH results in the productionof an alkyl acid. Examples of alkyl acids containing, or consisting of—(CH₂)₀₋₂₀—COOH include, but are not limited to, 2-norbornane aceticacid, tert-butyric acid and 3-cyclopentyl propionic acid.

“Heteroalkyl” refers to an alkyl wherein one of more of the carbon atomsin the hydrocarbon group is replaced with one or more of the followinggroups: amino, amido, —O—, —S— or carbonyl. In different embodiments 1or 2 heteroatoms are present.

“Substituted heteroalkyl” refers to a heteroalkyl wherein one or morehydrogen atoms of the hydrocarbon group is replaced with one or moresubstituents selected from the group consisting of halogen (i.e.,fluorine, chlorine, bromine and iodine), —OH, —CN, —SH, —NH₂, —NHCH₃,—NO₂, —C₁₋₂₀ alkyl substituted with 1 to 6 halogens, —CF₃, —OCH₃, —OCF₃and —(CH₂)₀₋₂₀—COOH. In different embodiments 1, 2, 3 or 4 substituentsare present.

“Alkenyl” refers to a hydrocarbon group made up of two or more carbonswhere one or more carbon-carbon double bonds are present. The alkenylhydrocarbon group may be straight-chain or contain one or more branchesor cyclic groups.

“Substituted alkenyl” refers to an alkenyl wherein one or more hydrogensare replaced with one or more substituents selected from the groupconsisting of halogen (i.e., fluorine, chlorine, bromine and iodine),—OH, —CN, —SH, —NH₂, —NHCH₃, —NO₂, —C₁₋₂₀ alkyl substituted with 1 to 6halogens, —CF₃, —OCH₃, —OCF₃ and —(CH₂)₀₋₂₀—COOH. In differentembodiments 1, 2, 3 or 4 substituents are present.

“Aryl” refers to an optionally substituted aromatic group with at leastone ring having a conjugated n-electron system, containing up to twoconjugated or fused ring systems. Aryl includes, but is not limited to,carboxylic aryl, heterocyclic aryl and biaryl groups. Preferably, thearyl is a 5- or 6-membered ring. Preferred atoms for a heterocyclic arylare one or more sulfur, oxygen and/or nitrogen. Examples of arylinclude, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, indole,quinoline, 2-imidazole and 9-anthracene. Aryl substituents are selectedfrom the group consisting of —C₁₋₂₀ alkyl, —C₁₋₂₀ alkoxy, halogen (i.e.,fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH₂, —NO₂,—C₁₋₂₀ alkyl substituted with 1 to 5 halogens, —CF₃, —OCF₃ and—(CH₂)₀₋₂₀—COOH. In different embodiments the aryl contains 0, 1, 2, 3or 4 substituents.

The term “halo” encompasses fluoro, chloro, bromo and iodo.

The term “(C₁-C₁₂)hydrocarbon moiety” encompasses alkyl, alkenyl andalkynyl and in the case of alkenyl and alkynyl there are C₂-C₁₂.

“Alkylaryl” refers to an “alkyl” joined to an “aryl”.

What is meant by Glu(O-hexyl) is

What is meant by Asp(1-heptanol) is

What is meant by Glu(1-heptanol) is

What is meant by Asp(NH-hexyl) is

What is meant by Glu(NH-hexyl) is

What is meant by Ser(n-octanoyl) or Ser(C(O)-heptyl) is

What is meant by Dap(1-octanesulfonyl) is

What is meant by Cys(R¹⁵) is:

What is meant by Cys(S-heptyl) is

What is meant by Dap(octanoyl) is

What is meant by biotinyl is

What is meant by myristyl is

What is meant by Lys(biotinyl) is

What is meant by Lys(myristyl) is

What is meant by Gly(myristyl) is

The present invention includes diastereomers as well as their racemicand resolved enantiomerically pure forms. Ghrelin analogs can containD-amino acids, L-amino acids or a combination thereof. Preferably, aminoacids present in a ghrelin analog are the L-enantiomers.

Preferred derivatives of analogs of the invention comprise D-aminoacids, N-alkyl-amino acids, β-amino acids and/or one or more labeledamino acids (including a labeled version of a D-amino acid,N-alkyl-amino acids, or a β-amino acid). A labeled derivative indicatesthe alteration of an amino acid or amino acid derivative with adetectable label. Examples of detectable labels include luminescent,enzymatic and radioactive labels. Both the type of label and theposition of the label can affect analog activity. Labels should beselected and positioned so as not to substantially alter the activity ofthe ghrelin analog at the GHS receptor. The effect of a particular labeland position on ghrelin activity can be determined using assaysmeasuring ghrelin activity and/or binding.

A protecting group covalently joined to the C-terminal carboxy groupreduces the reactivity of the carboxy terminus under in vivo conditions.The carboxy terminus protecting group is preferably attached to theα-carbonyl group of the last amino acid. Preferred carboxy terminusprotecting groups include amide, methylamide and ethylamide.

Certain other abbreviations used herein are defined as follows:

Nomenclature and Abbreviations Symbol Meaning Boc: tert-butyloxycarbonylBSA: bovine serum albumin Bzl: benzyl DCM: dichloromethane DIC:N,N-diisopropylcarbodiimide DIEA: diisopropylethyl amine Dmab:4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3- methylbutyl)-amino}benzyl DMAP: 4-(dimethylamino)pyridine DMF: dimethylformamide DNP:2,4-dinitrophenyl EDTA ethylenediaminetetracetic acid Fmoc:fluorenylmethyloxycarbonyl HBTU:2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphatecHex cyclohexyl HOAT:O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HOBt: 1-hydroxy-benzotriazole HPLC: high performanceliquid chromatography MBHA 4-methylbenzhydrylamine Mmt: 4-methoxytritylNMP: N-methylpyrrolidone Pbf:2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl PhiPrγ-2-phenylisopropyl ester PyAOP:7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium-hexafluorophosphate tBu: tert-butyl TIS: triisopropylsilane TOS: tosyltrt trityl TFA: trifluoro acetic acid TFFH:tetramethylfluoroforamidinium hexafluorophosphate Z: benzyloxycarbonyl

Synthetic Methods

The compounds of the invention can be produced using the techniquesdisclosed in the examples herein as well as techniques that are wellknown in the art. For example, a polypeptide region of a ghrelin analogcan be chemically or biochemically synthesized and modified. Examples oftechniques for biochemical synthesis involving the introduction of anucleic acid into a cell and expression of nucleic acids are provided inAusubel, Current Protocols in Molecular Biology, John Wiley, 1987-1998and Sambrook et al., in Molecular Cloning, A Laboratory Manual, 2ndEdition, Cold Spring Harbor Laboratory Press, 1989. Techniques forchemical synthesis of polypeptides are also well known in the art(Vincent in Peptide and Protein Drug Delivery, New York, N.Y., Dekker,1990). For example, the peptides of this invention can be prepared bystandard solid phase peptide synthesis (Stewart, J. M. et al., SolidPhase Synthesis, Pierce Chemical Co., 2d ed. 1984).

The substituents R² and R³ of the above generic formula may be attachedto the free amine of the N-terminal amino acid by standard methods knownin the art. For example, alkyl groups, e.g., (C₁-C₃₀)alkyl, may beattached using reductive alkylation. Hydroxyalkyl groups, e.g.,(C₁-C₃₀)hydroxyalkyl, may also be attached using reductive alkylationwherein the free hydroxy group is protected with a t-butyl ester. Acylgroups, e.g., COE¹, may be attached by coupling the free acid, e.g.,E¹COOH, to the free amine of the N-terminal amino acid by mixing thecompleted resin with 3 molar equivalents of both the free acid anddiisopropylcarbodiimide in methylene chloride for 1 hour. If the freeacid contains a free hydroxy group, e.g., p-hydroxyphenylpropionic acid,then the coupling should be performed with an additional 3 molarequivalents of HOBT.

When R¹ is NH—X²—CH₂—CONH₂, (i.e., Z⁰=CONH₂), the synthesis of thepeptide starts with Fmoc-HN—X²—CH₂—COOH coupled to a Rink Amide-MBHAresin (Amide-4-methylbenzylhydryl amine obtained from Novabiochem®, SanDiego, Calif.). If R¹ is NH—X²—CH₂—COOH (i.e., Z⁰—COOH) the synthesis ofthe peptide starts with Fmoc-HN—X²—CH₂—COOH which is coupled to Wangresin.

In the synthesis of a ghrelin analogue of this invention containing A5c,A6c and/or Aib, the coupling time is 2 hours for these residues and theresidue immediately following them.

Examples are provided below to further illustrate different features ofthe present invention. The examples also illustrate useful methodologyfor practicing the invention. These examples do not limit the claimedinvention.

EXAMPLE 158(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂(SEQ IDNO:118)

The title peptide was synthesized on an Applied Biosystems® model 433Apeptide synthesizer (obtained from Applied Biosystems®, Foster City,Calif., U.S.A.) using Fluorenylmethyloxycarbonyl (Fmoc) chemistry. ARink Amide-4-methylbenzylhydrylamine (MBHA) resin (obtained fromNovabiochem®, San Diego, Calif.) with substitution of 0.64 mmol/g wasemployed. The Fmoc amino acids (obtained from AnaSpec®, San Jose,Calif., U.S.A.) used were Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Aib-OH,Fmoc-Gln(Trt)-OH, Fmoc-Glu(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Leu-OH,Fmoc-Lys(Boc)-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH andFmoc-Val-OH. In addition, Fmoc-Glu(O-2-PhiPr)—OH (obtained fromNovabiochem®, San Diego, Calif.) was used for the amino acids in 3^(rd)and 17^(th) positions. The synthesis was carried out on a 0.1 mmolscale. The Fmoc groups were removed by treating the resin with asolution of 20% piperidine in N-methylpyrrolidone (NMP) for a period ofapproximately 30 minutes. In each coupling step, the Fmoc amino acid (3eq, 0.3 mmol) was first pre-activated in 2 mL solution of 0.45M2-(1-H-benzotriazole-1-yl)-1,1,2,3-tetramethyluronium-hexafluorophosphate/1-hydroxy-benzotriazole(HBTU/HOBT) in NMP. A solution containing the activated amino acid estertogether with 1 mL of diisopropylethylamine (DIEA) and 1 mL of NMP wasintroduced to the resin. The ABI 433A® peptide synthesizer wasprogrammed to perform the following reaction cycle:

(1) washing with NMP;(2) removing Fmoc protecting group with 20% piperidine in NMP for 30minutes;(3) washing with NMP; and(4) coupling with pre-activated Fmoc amino acid for approximately 1 or 3hours.The resin was coupled successively according to the sequence of thetitle peptide. After the peptide chain was assembled, the resin waswashed completely with N,N-dimethylformamide (DMF) and dichloromethane(DCM).

At the end of the assembly of the peptide chain on the ABI 433A® peptidesynthesizer (without the Fmoc-Aib residue in A¹), the peptide-resin wastransferred to a reaction vessel on a shaker and the Fmoc was removedusing 25% piperidine in DMF for 30 minutes. The resin was then washedwith DMF. The Fmoc-Aib-OH (0.4 mmole) was coupled using TFFH(Tetramethylfluoroformamidinium Hexafluorophosphate) (obtained fromPerceptive Biosystems®, Warrington, U.K.) (0.4 mmole), HOAt (0.4 mmol),DMAP (Dimethylaminopyridine) (0.1 g) and DIEA (1.2 mmole) once for 4hours and once overnight.

The Fmoc group was removed as above and the peptide was capped usingAc₂O (acetic anhydride) (5 mmole) and DIEA (5 mmole) in DMF forapproximately 30 minutes. The PhiPr (γ-2-phenylisopropyl ester) groupswere removed from the glutamine residues at A³ and A¹⁷ by washing with asolution of 3% TFA in DCM twice for a period of 10 minutes for eachwashing. The Boc that was partially removed from the side chain oflysine was replaced by using Boc₂O (0.8 mmole) and DIEA (0.8 mmole) inDCM overnight. The resin was treated with PyAOP(7-Azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium-hexafluorophosphate)(obtained from Applied Biosystems®, Foster City, Calif., U.S.A.) (0.6mmole), HOAt (0.6 mmole), DMAP (0.1 g) and DIEA (1.8 mmole) for 10minutes. Hexyl-NH₂(Hexylamine) (obtained from Sigma-Aldrich Chemicals®,St. Louis, Mo., U.S.A.) (2.0 mmole) was then added to the resin solutionwhich was then shaken and allowed to stand overnight.

To cleave the title peptide from the resin, the peptide-resin wastreated with a mixture of TFA, H₂O and triisopropylsilane (TIS) (9.5mL/0.85 mL/0.8 mL, respectively) for approximately 4 hours. The cleavedresin was filtered off and the remaining filtrate was poured into 200 mLof ether. A precipitate formed which was then collected bycentrifugation. The crude product was dissolved in a mixture ofacetonitrile and water which was purified on a reverse-phase preparativeHPLC system with a column (4×43 cm) of C₁₈ DYNAMAX-100 A⁰® (obtainedfrom Varian®, Walnut Creek, Calif., U.S.A.). The column was eluted overapproximately 1 hour using a linear gradient of 85% A:15% B to 60% A:40%B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. Thefractions were analyzed by HPLC and those fractions found to containpure product were pooled and lyophilized to dryness. Approximately 27.1mg (6.3%) of a white solid was recovered which was assayed using HPLCand found to be approximately 97.5% pure. Electro-spray ionization massspectrometry (ESI-MS) analysis determined the molecular weight to be3477.4 which was in agreement with the calculated molecular weight of3477.19.

EXAMPLE 70 (Aib^(1,2,10), Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂ (SEQID NO:50)

The titled peptide was synthesized according to the procedure describedfor Example 158, i.e., (Ac-Aib¹, Aib^(2,10),Glu(NH-Hexyl)^(3,17))hGhrelin(1-28)-NH₂) with the following exception:after coupling the last Fmoc-Aib-OH in the 1^(st) position on a shaker,the PhiPr protecting groups were removed from the glutamine residues atA³ and A¹⁷ by washing with a 3% TFA in DCM twice for intervals lastingapproximately 10 minutes. The Boc that was partially removed from theside chain of lysine was replaced using a solution of Boc₂O (0.8 mmole)and DIEA (0.8 mmole) in DCM. After being shaken and standing overnight,the resin was treated with a solution of PyAOP(7-Azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium-hexafluorophosphate)(obtained from Applied Biosystems®, Foster City, Calif., U.S.A.) (0.6mmole), HOAt (0.6 mmole), DMAP (0.1 g) and DIEA (1.8 mmole) for 10minutes after which Hexyl-NH₂(Hexylamine) (obtained from Sigma-Aldrich,St. Louis, Mo., U.S.A.) (2.0 mmole) was then added to the solution whichwas then shaken and allowed to stand overnight. The Fmoc protectinggroup was then removed using 25% piperidine in DMF. The peptide wascleaved off from the resin and purified on a HPLC system, as detailed inthe discussion of the synthesis of Example 158 above.

Using a HPLC assay, the purity of the resulting produce was found to beapproximately 96.5%. Electro-spray ionization mass spectrometry (ESI-MS)analysis determined the molecular weight to 3435.00 which was inagreement with the calculated molecular weight of 3435.16.

The following peptides of the invention can be prepared by a person ofordinary skill in the art using synthetic procedures analogous to thosedisclosed generally hereinabove:

Example 1: (Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:1) Example2: (Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:2) Example 3:(Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:3) Example 4:(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:4)Example 5: (Aib²,Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:5)Example 6: (Aib²,Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:6)Example 7: (Aib^(2,8),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:7)Example 8: (Aib^(2,8),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ IDNO:8) Example 9: (Aib^(2,10),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:9) Example 10: (Aib^(2,10),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂;(SEQ ID NO:10) Example 11: (Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQID NO:11) Example 12: (Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:12) Example 13: (Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ IDNO:13) Example 14: (Glu(NH-hexyl)315er(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂;(SEQ ID NO:14) Example 15: (Aib²,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂;(SEQ ID NO:15) Example 16:(Aib²,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:16) Example17: (Aib^(2,8),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:17)Example 18: (Aib^(2,8),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ IDNO:18) Example 19: (Aib^(2,10),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQID NO:19) Example 20:(Aib^(2,10),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:20)Example 21: (Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:21)Example 22: (Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:22) Example23: (Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:23) Example 24:(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:24)Example 25: (Dap(octanesulfonyl)¹⁷hGhrelin(1-28)-NH₂; (SEQ ID NO:25)Example 26: (Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:26) Example 27:(Dap(octanesulfonyl)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:27)Example 28: (Dap(octanesulfonyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:28) Example 29:(Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:29)Example 30: (Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:30)Example 31: (Cys(S-(CH₂)₉CH₃)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:31)Example 32: (Glu(NH-hexyl)³,Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:32) Example 33:(Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:33)Example 34: (Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:34) Example 35: (Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:35) Example 36:(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36) Example37: (Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)Example 38: (Aib²,4-Hyp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:37) Example 39: (Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:37) Example 40: (Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:37) Example 41:(Aib²,Tic⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37) Example42: (Aib²,Glu(NH-hexyl)^(3,17),Thz⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)Example 43: (Aib²,Glu(NH-hexyl)^(3,17),4-Hyp⁷,)hGhrelin(1-28)-NH₂; (SEQID NO:38) Example 44:(Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)Example 45: (Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:38) Example 46: (Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:38) Example 47:(Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:39) Example48: (Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)Example 49: (Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:41) Example 50: (Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:41) Example 51: (Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:41) Example 52:(Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NI-L; (SEQ ID NO:41) Example53: (Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)Example 54: (Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQID NO:42) Example 55:(Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)Example 56: (Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQID NO:42) Example 57: (Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:43) Example 58:(Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:44)Example 59: (Aib⁸,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:45)Example 60: (Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)Example 61: (3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)Example 62: (4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)Example 63: (2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)Example 64: (Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:47) Example 65: (Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQID NO:48) Example 66: (Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:48) Example 67:(Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48) Example68: (Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)Example 69: (Aib^(1,2,10)),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:49) Example 71: (A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:51) Example 72: (A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQID NO:52) Example 73: (Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQID NO:53) Example 74: (Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQID NO:54) Example 75: (Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:55) Example 76: (Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:56) Example 77: (Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQID NO:57) Example 78: (Lys(biotmyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)Example 79: (Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:59)Example 80: (Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:60) Example81: (Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:61) Example 82:(Glu(NH-hexyl)³,(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:62)Example 83: (Aib²,Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:63)Example 84: (Aib²,Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ IDNO:64) Example 85: (Aib^(2,8),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQID NO:65) Example 86:(Aib^(2,8),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:66)Example 87: (Aib^(2,10),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:67) Example 88: (Aib^(2,10),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂;(SEQ ID NO:68) Example 89: (Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQID NO:69) Example 90: (Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:70) Example 91: (Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ IDNO:71) Example 92: (Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:72) Example 93: (Aib²,Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:73) Example 94:(Aib²,Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:74) Example95: (Aib^(2,8),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:75)Example 96: (Aib^(2,8),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ IDNO:76) Example 97: (Aib^(2,10),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQID NO:77) Example 98:(Aib^(2,10),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:78)Example 99: (Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:79)Example 100: (Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:80) Example101: (Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:81) Example102: (Glu(NH-hexyl)³,Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:82) Example 103: (Aib²,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:83) Example 104: (Aib²,Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQID NO:84) Example 105: (Aib^(2,8),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂;(SEQ ID NO:85) Example 106:(Aib^(2,8),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:86)Example 107: (Aib^(2,10),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:87) Example 108: (Aib^(2,10),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂;(SEQ ID NO:88) Example 109: (Ac-Gly¹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:89) Example 110:(Ac-Gly¹,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:90) Example111: (Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:91)Example 112:(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:92) Example 113: (Ac-Gly¹,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:93) Example 114:(Ac-Gly¹,Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:94)Example 115:(Ac-Gly¹,Dap(octanesulfonyl)³,Glu(NH-Hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:95) Example 116:(Ac-Gly¹,Dap(octanesulfonyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:96) Example 117:(Ac-Gly¹,Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:97) Example 118: (Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:98) Example 119:(Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:99)Example 120:(Ac-Gly¹,Glu(NH-hexyl)³,(Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:100) Example 121:(Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:101) Example 122:(Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:102) Example 123: (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(hGhrelin(1-28)-NH)₂; (SEQ ID NO:103) Example 124:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:104)Example 125: (Ac-Gly¹,Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:105) Example 126:(Ac-Gly¹,Aib²,4-Hyp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:105)Example 127: (Ac-Gly¹,Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:105) Example 128:(Ac-Gly¹,Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:105)Example 129: (Ac-Gly¹,Aib²,Tic⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:105) Example 130:(Ac-Gly¹,Aib²,Glu(NH-hexyl)3,17,Thz˜hGhrelin(1-28)-NH₂; (SEQ ID NO:106)Example 131:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Hyp˜hGhrelin(1-28)-NH₂; (SEQ IDNO:106) Example 132:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:106) Example 133:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:106) Example 134:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:106) Example 135:(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:107)Example 136: (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:108) Example 137:(Ac-Gly¹,Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:109)Example 138: (Ac-Gly¹,Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:109) Example 139:(Ac-Gly¹,Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:109)Example 140: (Ac-Gly¹,Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:109) Example 141:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:110) Example 142:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:110) Example 143:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:110) Example 144:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:110) Example 145:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:111)Example 146:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:112) Example 147: (Ac-Gly¹,Aib⁸,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:113) Example 148:(Ac-Gly¹,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:114)Example 149: (Ac-Gly¹,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) Example 150: (Ac-Gly¹,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:114) Example 151:(Ac-Gly¹,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:114)Example 152: (Ac-Gly¹,Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQID NO:115) Example 153:(Ac-Gly¹,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:116)Example 154: (Ac-Gly¹,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:116) Example 155:(Ac-Gly¹,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:116)Example 156: (Ac-Gly¹,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:116) Example 157:(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:117)Example 159: (Ac-Gly¹,A5c₂,Glu(NH-hexyl)l˜hGhrelin(1-28)-NH₂; (SEQ IDNO:119) Example 160:(Ac-Gly¹,A5c₂,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:120)Example 161: (Ac-Gly¹,Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:121) Example 162: (Ac-Gly¹,Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:122) Example 163:(Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:123)Example 164: (Ac-Gly¹,Asp(NH-hexyl)3^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:124) Example 165:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:125)Example 166:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)³,Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126) Example 167:(Ac-Gly¹,Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:127) Example168: (Ac-Gly¹,Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:128)Example 169: (Ac-Gly¹,Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ IDNO:129) Example 170:(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:130) Example 171: (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂;(SEQ ID NO:131) Example 172:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:1312)Example 173: (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQID NO:133) Example 174:(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ IDNO:134) Example 175:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:135)Example 176:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ IDNO:136) Example 177: (Ac-Gly¹,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQID NO:137) Example 178: (Ac-Gly¹,Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂;(SEQ ID NO:138) Example 179:(Ac-Gly¹,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:139)Example 180:(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:140) Example 181: (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂;(SEQ ID NO:141) Example 182:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:142)Example 183: (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQID NO:143) Example 184:(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ IDNO:144) Example 185:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:145)Example 186:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ IDNO:146) Example 187: (Ac-Gly¹,Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQID NO:147) Example 188: (Ac-Gly¹,Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂;(SEQ ID NO:148) Example 189:(Ac-Gly¹,Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:149)Example 190:(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:150) Example 191: (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂;(SEQ ID NO:151) Example 192:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:152)Example 193: (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQID NO:153) Example 194:(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ IDNO:154) Example 195:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:155)Example 196: (Ac-Gly¹,Aib^(2,10),Glu(NH˜hexyl)3AS)hGhrelin(1˜28)˜NH₂;(SEQ ID NO:156) Example 197:(Ac-Gly¹,Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:157) Example198: (Ac-Gly¹,Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:158)Example 199: (Ac-Gly¹,Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ IDNO:159) Example 200:(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:160) Example 201: (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:161) Example 202:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:162)Example 203: (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQID NO:163) Example 204:(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ IDNO:164) Example 205:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:165)Example 206:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ IDNO:166) Example 207: (Ac-Gly¹,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQID NO:167) Example 208: (Ac-Gly¹,Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂;(SEQ ID NO:168) Example 209:(Ac-Gly¹,Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:169)Example 210:(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:170) Example 211: (Ac-Gly¹,Aib²,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂;(SEQ ID NO:171) Example 212:(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:172)Example 213: (Ac-Gly¹,Aib^(ZS,Glu(NH-hexyl)) ²⁰)hGhrelin(1-28)-NH₂; (SEQID NO:173) Example 214:(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ IDNO:174) Example 215: (Ac-Gly¹,Aib²⁰,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂;(SEQ ID NO:175) and Example 216:(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ IDNO:176) Example 217: (Aib²,Lys(mynstyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:177) and Example 218:(Gly(mynstyl)¹,Aib²,Lys(mynstyl)¹⁷)hGhrelin(1-28)-NH₂. (SEQ ID NO:178)Example 219: (Aib^(2,8),Ser³,Glu(NH-hexyl)¹⁷) hGrehlin(1-28)-NH₂ (SEQ IDNO:180)

A selection of the preferred embodiments listed above was analyzed byelectro-spray ionization mass spectrometry (ESI-MS) to determinemolecular weight. Table 1 presented below reports the data compiledduring this testing. The purity of each of the selected compounds,assayed using HPLC, is also provided in Tables 1A, 1B, 1C, and 1D.

TABLE 1A Molecular Weight and Purity of Selected Compounds MolecularMolecular Weight Weight Purity Example # COMPOUND (Calculated) (MS-ES)(%) #48 (Aib^(2,8),Glu(NH- 3406.12 3405.70 99.9% (SEQ IDhexyl)^(3,17))hGhrelin(1-28)-NH₂ NO: 40) #136 (Ac-Gly¹,Aib^(2,8),Glu(NH-3448.16 3447.98 98.0% (SEQ ID hexyl)^(3,17))hGhrelin(1-28)-NH₂ NO: 108)#124 (Ac-Gly¹,Aib²,Glu(NH- 3492.17 3492.00 99.0% (SEQ IDhexyl)^(3,17))hGhrelin(1-28)-NH₂ NO: 104) #166(Ac-Gly¹,Aib^(2,10),Glu(NH- 3591.32 3591.50 98.4% (SEQ IDhexyl)³,Lys(biotinyl)¹⁷)hGhrelin(1- NO: 126) 28)-NH₂ #70(Aib^(1,2,10),Glu(NH- 3435.16 3435.00 96.5% (SEQ IDhexyl)^(3,17))hGhrelin(1-28)-NH₂ NO: 50) #158(Ac-Aib¹,Aib^(2,10),Glu(NH- 3477.19 3477.40 97.5% (SEQ IDhexyl)^(3,17))hGhrelin(1-28)-NH₂ NO: 118) #146(Ac-Gly¹,Aib^(2,10),Glu(NH- 3449.14 3449.20 99.0% (SEQ IDhexyl)^(3,17))hGhrelin(1-28)-NH₂ NO: 112) #78(Lys(biotinyl)¹⁷)hGhrelin(1-28)- 3595.27 3594.90 97.7% (SEQ ID NH₂ NO:58)

TABLE 1B Molecular Weight and Purity of Selected Compounds MolecularMolecular Weight Weight Purity Example # COMPOUND (Calculated) (MS-ES)(%) #217 (Aib²,Lys(myristyl)¹⁷)hGhrelin(1- 3577.35 3577.2 99.2% (SEQ ID28)-NH₂ NO: 177) #218(Gly(myristyl)¹,Aib²,Lys(myristyl)¹⁷)hGhrelin(1-28)- 3787.71 3788.298.6% (SEQ ID NH₂ NO: 178)

TABLE 1C Molecular Weight and Purity of Selected Compounds MolecularMolecular Weight Weight Purity Example # COMPOUND (Calculated) (MS-ES)(%) #58 (Aib^(2,10),Glu(NH- 3407.10 3407.20 100% (SEQ IDhexyl)^(3,17))hGhrelin(1-28)-NH₂ NO: 44)

TABLE 1D Molecular Weight and Purity of Selected Compounds MolecularMolecular Weight Weight Purity Example # COMPOUND (Calculated) (MS-ES)(%) #219 (Aib^(2,8),Ser³,Glu(NH-hexyl)¹⁷) 3280.91 3281.60 99.0% (SEQ IDhGhrelin(1-28)-NH₂ NO: 180)

Determination of Biological Activity GHS Receptor Binding DeterminationAssay

The activity of the compounds of the invention at the GHS receptor canbe and were determined using techniques such as those described in theexamples provided below. In different embodiments, a ghrelin analog hasat least about 50%, at least about 60%, at least about 70%, at leastabout 80% at least about 90%, at least about 95%, at least about 98% ormore, functional activity relative to ghrelin as determined using one ormore of the functional activity assays described below; and/or has anIC₅₀ greater than about 1,000 nM, greater than about 100 nM, or greaterthan about 50 nM, using the receptor binding assay described below. Withrespect to IC₅₀, greater refers to potency and thus indicates a lesseramount is needed to achieve binding inhibition.

Assays measuring the ability of a compound to bind a GHS receptor employa GHS receptor, a fragment of the receptor comprising a ghrelin bindingsite, a polypeptide comprising such a fragment, or a derivative of thepolypeptide. Preferably, the assay uses the GHS receptor or a fragmentthereof.

A polypeptide comprising a GHS receptor fragment that binds ghrelin canalso contain one or more polypeptide regions not found in a GHSreceptor. A derivative of such a polypeptide comprises a GHS receptorfragment that binds ghrelin along with one or more non-peptidecomponents.

The GHS receptor amino acid sequence involved in ghrelin binding can bereadily identified using labeled ghrelin or ghrelin analogs anddifferent receptor fragments. Different strategies can be employed toselect fragments to be tested to narrow down the binding region.Examples of such strategies include, but are not limited to, testingconsecutive fragments about 15 amino acids in length starting at theN-terminus and testing longer length fragments. If longer lengthfragments are tested, a fragment binding ghrelin can be subdivided tofurther locate the ghrelin binding region. Fragments used for bindingstudies can be generated using recombinant nucleic acid techniques.

Binding assays can be performed using individual compounds orpreparations containing different numbers of compounds. A preparationcontaining different numbers of compounds having the ability to bind tothe GHS receptor can be divided into smaller groups of compounds thatcan be tested to identify the compound(s) binding to the GHS receptor.In an embodiment of the present invention, a test preparation containingat least 10 compounds is used in a binding assay.

Binding assays can be performed using recombinantly produced GHSreceptor polypeptides present in different environments. Suchenvironments include, for example, cell extracts and purified cellextracts containing the GHS receptor polypeptide expressed fromrecombinant nucleic acid or naturally occurring nucleic acid; and alsoinclude, for example, the use of a purified GHS receptor polypeptideproduced by recombinant means or from naturally occurring nucleic acidwhich is introduced into a different environment.

Screening for GHS Receptor Active Compounds

Screening for GHS receptor active compounds is facilitated using arecombinantly expressed receptor. A recombinantly expressed GHS receptoroffers several advantages such as the ability to express the receptor ina defined cell system so that a response to a compound at the GHSreceptor can more readily be differentiated from responses at otherreceptors. For example, the GHS receptor can be expressed in a cell linesuch as HEK 293, COS 7 and CHO not normally expressing the receptor byan expression vector wherein the same cell line without the expressionvector can act as a control.

Screening for compounds reducing GHS receptor activity is facilitatedusing a ghrelin analog in the assay which provides for GHS receptoractivity. The effect of test compounds on such activity can be measuredto identify, for example, allosteric modulators and antagonists.

GHS receptor activity can be measured using different techniques such asdetecting a change in the intracellular conformation of the GHSreceptor, in the G-protein coupled activities and/or in theintracellular messengers. Preferably, GHS receptor activity is measuredusing techniques such as those measuring intracellular Ca²⁺. Examples oftechniques well known in the art that can be employed to measure Ca²⁺include the use of dyes such as Fura-2 and the use ofCa²⁺-bioluminescent sensitive reporter proteins such as aequorin. Anexample of a cell line employing aequorin to measure G-protein activityis HEK293/aeq17 (Button, D. et al., Cell Calcium, (1993), 14(9):663-71;and Feighner, S. D. et al., Science, (1999), 284(5423):2184-8).

Chimeric receptors containing a ghrelin binding region functionallycoupled to a different G-protein can also be used to measure GHSreceptor activity. A chimeric GHS receptor contains an N-terminalextracellular domain, a transmembrane domain made up of transmembraneregions, extracellular loop regions and intracellular loop regions andan intracellular carboxy terminus. Techniques for producing chimericreceptors and measuring G-protein coupled responses are provided in, forexample, International Patent Application No. PCT/US96/12336 [WO97/05252] and U.S. Pat. No. 5,264,565 incorporated herein by reference.

Stimulation of GHS Receptor Activity

Ghrelin analogs can be used to stimulate GHS receptor activity which canbe used, for example, to study the effects of GHS receptor modulationand/or GH secretion, to identify ghrelin antagonists and/or to benefit asubject suffering from a disease or condition such as a GH-deficientstate, diminished muscle mass and/or bone density, sexual dysfunction,unhealthy body weight, loss of motor skills and/or physical functioningand/or a lack of normal appetite.

Increasing weight or appetite is crucial in maintaining an ideal,healthy body weight in an individual susceptible to weight loss, such asthe sick or elderly. Loss of weight or appetite in an under weightsubject can lead to serious health problems. In a patient suffering froma disease or undergoing a medical treatment which causes weight lossand/or a lack of normal appetite, the effectiveness of the treatment ofsaid disease or condition is contingent upon the patient's ability tomaintain a consistent weight. Underweight subjects include those havinga body weight about 10% or less, 20% or less, or 30% or less, than thelower end of a “normal” weight range or Body Mass Index (“BMI”) which isdetermined by calculating weight in kilograms divided by the square ofheight in meters. The BMI “normal” range, which is well known in theart, is 19-22. Individuals whose body-mass index falls below the“normal” range are more susceptible to disease and certain beneficialmedical treatments such as chemotherapy, are less effective inindividuals having a subnormal BMI.

Biological Assays—Examples 1. Receptor Binding Assay A. Preparation ofCHO-K1 Cells Expressing the Human Recombinant GHS Receptor

The cDNA for human GH secretagogue receptor (hGHS—R or ghrelin receptor)was cloned using Polymerase Chain Reaction (PCR) techniques well knownto those skilled in the art wherein human brain RNA was employed as atemplate (obtained from Clontech®, Palo Alto, Calif., U.S.A.), genespecific primers flanking the full-length coding sequence of hGHS—R(S:5′-A T G T G G A A C G C G A C G C C C A G C G A A G A G-3′ and AS:5′-T C A T G T A T T A A T A C T A G A T T C T G T C C A-3′) andAdvantage 2 PCR Kit® (available from Clontech®, Palo Alto, Calif.,U.S.A.). The PCR product was cloned into the pCR2.1 vector usingOriginal TA Cloning Kit® (obtained from Invitrogen®, Carlsbad, Calif.,U.S.A.). The full length human GHS—R was subcloned into the mammalianexpression vector pcDNA 3.1 (available from Invitrogen®, Carlsbad,Calif., U.S.A.). The plasmid was transfected into the Chinese hamsterovary cell line, CHO-K1 (provided by American Type Culture Collection®,Rockville, Md., U.S.A.) using known calcium phosphate methods asdescribed in Wigler, M. et al., Cell, (1977), 11(1):223-32. Single cellclones stably expressing the hGHS—R were obtained by selectingtransfected cells grown in cloning rings in RPMI 1640 media supplementedwith 10% fetal bovine serum and 1 mM sodium pyruvate containing 0.8mg/ml G418 (purchased from Gibco®, Grand Island, N.Y., U.S.A.).

B. GHS—R Binding Assay:

Membranes for radioligand binding studies can be and were prepared byhomogenization of the foregoing CHO-K1 cells expressing the humanrecombinant GHS receptor in about 20 ml of ice-cold 50 mM Tris-HCl witha Brinkman Polytron® (Brinkman®, Westbury, N.Y., U.S.A.) at setting 6for about 15 seconds. The homogenates were washed twice bycentrifugation (39,000 g/10 minutes) and the final pellets wereresuspended in about 50 mM Tris-HCl containing 2.5 mM MgCl₂ and 0.1%bovine serum albumin (BSA). For the selected assay, aliquots ofapproximately 0.4 ml were incubated with 0.05 nM (¹²⁵I)ghrelin (˜2000Ci/mmol; Perkin Elmer Life Sciences@, Boston, Mass., U.S.A.) with andwithout 0.05 ml of unlabeled competing test peptide. After approximately60 minutes at 4° C., the bound (¹²⁵I)ghrelin was separated from the freeghrelin by rapid filtration through GF/C filters (available fromBrandel®, Gaithersburg, Md., U.S.A.) which were pre-soaked in 0.5%polyethyleneimine/0.1% BSA. The filters were then washed 3 times with5-ml aliquots of ice-cold 50 mM Tris-HCl and 0.1% BSA. The boundradioactivity trapped on the filters was counted by gamma spectrometry(using a spectrometer from Wallace LKB®, Gaithersburg, Md., U.S.A.).Specific binding was determined by subtracting (¹²⁵I)ghrelin bound inthe presence of 1000 nM ghrelin (available from Bachem®, Torrence,Calif., U.S.A.) from the total (¹²⁵I)ghrelin bound.

A selection of the preferred embodiments was tested using the receptorbinding assay discussed above and the results are reported in Table 2presented below.

TABLE 2 Receptor Binding Ki Values for Selected Compounds Example #COMPOUND Ki(nM) #48 (Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂0.45 (SEQ ID NO: 40) #136(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂ 2.94 (SEQ IDNO: 108) #124 (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂ 1.68(SEQ ID NO: 104) #166(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)³,Lys(biotinyl)¹⁷)hGhrelin(1- 1.28 (SEQID 28)-NH₂ NO: 126) #70(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂ 0.63 (SEQ ID NO:50) #158 (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂24.44 (SEQ ID NO: 118) #146(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂ 0.99 (SEQ IDNO: 112) #78 (Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂ 0.07 (SEQ ID NO: 58)#58 (Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂ 0.40 (SEQ ID NO:44) #217 (Aib²,Lys(myristyl)¹⁷)hGhrelin(1-28)-NH₂ 0.16 (SEQ ID NO: 177)#219 (Aib^(2,8),Ser³,Glu(NH-hexyl)¹⁷)hGrehlin(1-28)-NH₂ 214 (SEQ ID NO:180)

2. GHS—R Functional Activity Assays

A. In vitro GSH Receptor Mediated Intracellular iCa²⁺ Mobilization

The foregoing CHO-K1 cells expressing the human GSH receptor wereharvested by incubating in a 0.3% EDTA/phosphate buffered salinesolution at 25° C.; the cells were then washed 2 times bycentrifugation. The washed cells were resuspended in Hank's bufferedsaline solution (HBSS) for loading of the fluorescent Ca²⁺ indicatorFura-2AM. Cell suspensions of approximately 10⁶ cells/ml were incubatedwith 2 μM Fura-2AM for about 30 minutes at about 25° C. UnloadedFura-2AM was removed by centrifugation twice in HBSS and the finalsuspensions were transferred to a spectrofluorometer (model HitachiF-2000® Tokyo, Japan) equipped with a magnetic stirring mechanism and atemperature-regulated cuvette holder. After equilibration to 37° C., theghrelin analogs were added for measurement of intracellular Ca²⁺mobilization. The excitation and emission wavelengths were 340 and 510nm, respectively. Using this analysis method, compounds of Examples 124and 136 were found to exhibit antagonistic activity at the ghrelinreceptor.

B. In Vivo GH Release/Suppression

As is well known in the art, compounds may be tested for their abilityto stimulate or suppress release of GH in vivo. (Deghenghi, R. et al.,Life Sciences, (1994), 54(18):1321-8; and International PatentApplication No. PCT/EP01/07929 [WO 02/08250]). In order to ascertain acompound's ability to stimulate GH release in vivo, the selectedcompound at a dosage of approximately 300 mg/kg is injectedsubcutaneously in 10-day old rats. The circulating GH is measuredapproximately 15 minutes after injection and compared to GH levels inrats injected with a solvent control.

Similarly, selected compounds may be tested for their ability toantagonize ghrelin-induced GH secretion in vivo. A 300 mg/kg dose of acompound of the instant application should be injected subcutaneously in10-day old rats along with ghrelin. The circulating GH is then measureapproximately 15 minutes after injection and compared to GH levels inrats injected with ghrelin alone.

Administration

Ghrelin analogs can be formulated and administered to a subject usingthe guidance provided herein along with techniques well known in theart. The preferred route of administration ensures that an effectiveamount of compound reaches the target. Guidelines for pharmaceuticaladministration in general are provided in, for example, Remington'sPharmaceutical Sciences 18th Edition, Ed. Gennaro, Mack Publishing,1990, and Modem Pharmaceutics 2nd Edition, Eds. Banker and Rhodes,Marcel Dekker, Inc., 1990, both of which are hereby incorporated byreference.

Ghrelin analogs can be prepared as acidic or basic salts.Pharmaceutically acceptable salts (in the form of water- or oil-solubleor dispersible products) include conventional non-toxic salts or thequaternary ammonium salts formed from inorganic or organic acids orbases. Examples of such salts include, but are not limited to, acidaddition salts such as acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate;and base salts such as ammonium salts, alkali metal salts such as sodiumand potassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine and salts with amino acids such as arginineand lysine.

Ghrelin analogs can be administered using different routes includingoral and nasal ingestion or by transdermal and transmucosal injection.Active ingredients administered orally as a suspension can be preparedaccording to techniques well known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer and sweeteners/flavoring agents.As immediate release tablets, pharmaceutical formulations may containmicrocrystalline cellulose, dicalcium phosphate, starch, magnesiumstearate and lactose and/or other excipients, binders, extenders,disintegrants, diluents and lubricants.

Administered by nasal aerosol or inhalation formulations may beprepared, for example, as solutions in saline, employing benzyl alcoholor other suitable preservatives, absorption promoters to enhancebioavailability, employing fluorocarbons and/or employing othersolubilizing or dispersing agents.

Ghrelin analogs may also be administered in intravenously (both bolusand infusion), intraperitoneally, subcutaneously, topically, with orwithout occlusion, or intramuscularly. When administered by injection,the injectable solution or suspension may be formulated using suitablenon-toxic, parenterally-acceptable diluents or solvents, such asRinger's solution or isotonic sodium chloride solution, or suitabledispersing or wetting and suspending agents, such as sterile, bland,fixed oils, including synthetic mono- or diglycerides and fatty acids,including oleic acid.

Suitable dosing regimens are preferably determined taking into accountfactors well known in the art including type of subject being dosed;age, weight, sex and medical condition of the subject; the route ofadministration; the renal and hepatic function of the subject; thedesired effect; and the particular compound employed.

Optimal precision in achieving concentrations of drug within the rangethat yields efficacy without toxicity requires a regimen based on thekinetics of the drug's availability to target sites. This involves aconsideration of the distribution, equilibrium, and elimination of adrug. The daily dose for a subject is expected to be between 0.01 and1,000 mg per subject per day.

Ghrelin analogs can be provided in a kit. Such a kit typically containsan active compound in dosage forms for administration. A dosage formcontains a sufficient amount of active compound such that a desirableeffect can be obtained when administered to a subject during regularintervals, such as 1 to 6 times a day, during the course of 1 or moredays. Preferably, a kit contains instructions indicating the use of thedosage form to achieve a desirable affect and the amount of dosage formto be taken over a specified time period.

The invention has been described in an illustrative manner, and it is tobe understood that the terminology which has been used is intended to bein the nature of words of description rather than of limitation.Obviously, many modifications and variations of the present inventionare possible in light of the above teachings. It is, therefore, to beunderstood that within the scope of the appended claims the inventionmay be practiced otherwise than as specifically described.

The patent and scientific literature referred to herein representsknowledge that is available to those with skill in the art. All patents,patent publications and other publications cited herein are herebyincorporated by reference in their entirety.

1. A compound according to formula (I):(R²R³)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵A²⁶-A²⁷- A²⁸-R¹ (I)

wherein: A¹ is Gly, Acc, Aib, Ala or β-Ala or Acc; A² is Ser, Aib, Ala,Acc, Abu, Act, Ava, Thr or Val; A³ is Ser, Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶),Ser(C(O)—R⁴), Thr(C(O)—R⁵) or HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); A⁴ isPhe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe,(X¹,X²,X³,X⁴,X⁵)Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr; A⁵ is Leu, Abu, Acc,Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle or Val; A⁶ is Ser, Abu,Acc, Act, Aib, Ala, Gly, Thr or Val; A⁷ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp,Inc, Ktp, Oic, Pip, Thz or Tic; A⁸ is Glu, Acc, Aib, Arg, Asn, Asp, Dab,Dap, Gln, Lys, Orn or HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); A⁹ is His, Apc,Aib, Acc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, (X¹,X²,X³,X⁴,X⁵—)Phe, Taz, 2-Thior 3-Thi; A¹⁰ is Gln, Acc, Aib, Asn, Asp or Glu; A¹¹ is Arg, Apc, hArg,Dab, Dap, Lys, Om or HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); A¹² is Val, Abu,Acc, Aib, Ala, Cha, Nva, Gly, Ile, Leu, Nle or Tle; A¹³ is Gln, Acc,Aib, Asn, Asp or Glu; A¹⁴ is Gln, Acc, Aib, Asn, Asp or Glu; A¹⁵ is Arg,hArg, Acc, Aib, Apc, Dab, Dap, Lys, Om, Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); A¹⁶ is Lys, Acc, Aib, Apc, Arg, hArg,Dab, Dap, Orn, Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶),hCys(R¹⁷), Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷, Glu(O—R⁶),Ser(C(O)—R⁴), Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;A⁷ is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Lys(biotinyl), Ser(C(O)—R⁴),Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted; A¹⁸ is Ser,Abu, Acc, Act, Aib, Ala, Thr, Val, Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴),Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹⁰),Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted; A¹⁹ is Lys, Acc, Aib, Apc,Arg, hArg, Dab, Dap, Orn, Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵),hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷),Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O)or deleted; A²⁰ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn,Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷),Dab(S(O)₂—R⁷), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴),Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted; A²¹ is Pro,Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted; A²² isPro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;A²³ is Ala, Abu, Acc, Act, Aib, Apc, Gly, Nva, Val or deleted; A²⁴ isLys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn,HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted; A²⁵ is Leu, Abu, Acc, Aib,Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val or deleted; A²⁶ is Gln,Aib, Asn, Asp, Glu or deleted; A²⁷ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc,Ktp, Oic, Pip, Thz, Tic or deleted; A²⁸ is Arg, Acc, Aib, Apc, hArg,Dab, Dap, Lys, Orn, HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted; R¹ is—OH, —NH₂, —(C₁-C₃₀)alkoxy or NH—X⁶—CH₂-Z⁰, wherein X⁶ is a(C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl and Z⁰ is —H, —OH, —CO₂H or —C(O)—NH₂; R²and R³ is, independently for each occurrence thereof, selected from thegroup consisting of H, (C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl,(C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl,substituted (C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted(C₂-C₃₀)acyl, substituted (C₂-C₃₀)alkenyl, substituted aryl(C₁-C₃₀)alkyland substituted aryl(C₁-C₃₀)acyl; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴,R¹⁵, R¹⁶ and R¹⁷ is, independently for each occurrence thereof, selectedfrom the group consisting of (C₁-C₄₀)alkyl, (C₂-C₄₀)alkenyl, substituted(C₁-C₄₀) alkyl, substituted (C₂-C₄₀) alkenyl, alkylaryl, substitutedalkylaryl, aryl and substituted aryl; R¹² and R¹³ is, independently foreach occurrence thereof, selected from the group consisting of H,(C₁-C₄₀)alkyl, (C₁-C₄₀)acyl, (C₁-C₃₀)alkylsulfonyl, biotinyl and—C(NH)—NH₂, X¹, X², X³, X⁴, and X⁵ is, independently for each occurrencethereof, selected from the group consisting of H, F, Cl, Br, I,(C₁₋₁₀)alkyl, substituted (C₁₋₁₀)alkyl, aryl, substituted aryl, OH, NH₂,NO₂ and CN; and n is, independently for each occurrence thereof, 1, 2,3, 4 or 5; provided that: (I). if R² is (C₁-C₃₀)acyl, aryl(—C₁-C₃₀)acyl,substituted (C₂-C₃₀)acyl, or substituted aryl(C₁-C₃₀)acyl, then R³ is H,(C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, aryl(C₁-C₃₀)alkyl,substituted (C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted(C₂-C₃₀)alkenyl or substituted aryl(C₁-C₃₀)alkyl; (II). if R¹² is(C₁-C₄₀)acyl, (C₁-C₃₀)alkylsulfonyl, biotinyl or —C(NH)—NH₂, then R¹³ isH or (C₁-C₄₀)alkyl; (III). at least one of A¹⁵, A¹⁶, A¹⁷, A¹⁸, A¹⁹ orA²⁰ must be selected from the group consisting of Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) andHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); and (IV). if any member of the groupconsisting of A¹⁵, A¹⁶, A¹⁷, A¹⁹ and A²⁰ isHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O), then R¹² must be biotinyl; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein: A¹ is Gly or Aib; A² is Ser, Act, Aib, Ava or A5c; A³is Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷),Glu(O—R⁶) or Ser(C(O)—R⁴); A⁴ is Phe; A⁵ is Leu, Acc, Aib, Cha or hLeu;A⁶ is Ser, Abu, Act, Aib or Thr; A⁷ is Pro, Dhp, Dmt, 4-Hyp, Ktp, Pip,Thz or Tic; A⁸ is Glu or Aib; A⁹ is His, Aib, Apc, 2-Fua, 2-Pal, 3-Pal,4-Pal, Taz or 2-Thi; A¹⁰ is Gln or Aib; A¹¹ is Arg; A¹² is Val or Acc;A¹³ is Gln; A¹⁴ is Gln; A¹⁵ is Arg, Orn, Glu(NH—R⁷) or Ser(C(O)—R⁴); A¹⁶is Lys, Apc, Glu(NH—R⁷) or Ser(C(O)—R⁴); A¹⁷ is Glu, Lys(biotinyl),Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷),Glu(O—R⁶), Ser(C(O)—R⁴) or HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); A¹⁸ is Ser;A¹⁹ is Lys, Glu(NH—R⁷) or Ser(C(O)—R⁴); A²⁰ is Lys, Glu(NH—R⁷) orSer(C(O)—R⁴); A²¹ is Pro; A²² is Pro; A²³ is Ala; A²⁴ is Lys; A²⁵ isLeu; A²⁶ is Gln; A²⁷ is Pro; and A²⁸ is Arg; or a pharmaceuticallyacceptable salt thereof.
 3. A compound according to claim 2, wherein: R²and R³ is, independently for each occurrence thereof, selected from thegroup consisting of H, (C₁-C₆)acyl, n-butyryl, isobutyryl andn-octanoyl; R⁴ is heptyl; R⁶ is hexyl; R⁷ is hexyl; R¹⁰ is octyl; R¹¹ isheptyl; and Acc is, independently for each occurrence thereof, selectedfrom the group consisting of A3c, A4c, A5c and A6c; or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 3, wherein: A³ is Asp(NH-hexyl), Asp(1-heptanol),Cys(S—(CH₂)₉CH₃), Dap(octanesulfonyl), Glu(NH-hexyl) or Glu(1-heptanol);A⁵ is Leu; A⁶ is Ser; A⁷ is Pro, Dhp, 4-Hyp, Pip, Thz or Tic; A⁹ is His,3-Pal, 4-Pal, Taz or 2-Thi; A¹² is Val; A¹⁵ is Arg, Glu(NH-hexyl) orSer(n-octanoyl); A¹⁶ is Lys, Glu(NH-hexyl) or Ser(n-octanoyl); A¹⁷ isGlu, Lys(biotinyl), Asp(NH-hexyl), Asp(1-heptanol), Cys(S—(CH₂)₉CH₃),Dap(octanesulfonyl), Glu-(NH-hexyl), Glu(1-heptanol) or Ser(n-octanoyl);A¹⁸ is Ser, Glu(NH-hexyl) or Ser(n-octanoyl); A¹⁹ is Lys, Glu(NH-hexyl)or Ser(n-octanoyl); A²⁰ is Lys, Glu(NH-hexyl) or Ser(n-octanoyl); or apharmaceutically acceptable salt thereof.
 5. A compound according toclaim 4, wherein said compound is:(Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:1)(Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:2)(Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:3)(Glu(NH-hexyl)³,Ser(n-Octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:4)(Aib²,Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:5)(Aib²,Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:6)(Aib^(2,8),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:7)(Aib^(2,8),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:8)(Aib^(2,10),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:9)(Aib^(2,10),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:10)(Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:11)(Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:12)(Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:13)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:14)(Aib²,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:15)(Aib²,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:16)(Aib^(2,8),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:17)(Aib^(2,8),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:18)(Aib^(2,10),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:19)(Aib^(2,10),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:20)(Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:21)(Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:22)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:23)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH²; (SEQ ID NO:24)(Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:25)(Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:26)(Dap(octanesulfonyl)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:27)(Dap(octanesulfonyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:28) (Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:29) (Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:30)(Cys(S-(CH₂)₉CH₃)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:31)(Glu(NH-hexyl)³,(Cys(S-(CH₂)⁹CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:32)(Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:33)(Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:34)(Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:35)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,4-Hyp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Tic⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Glu(NH-hexyl)^(3,17),Thz⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),4-Hyp⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:39)(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhre1in(1-28)-NH₂; (SEQ ID NO:40)(Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:43)(Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:44)(Aib⁸,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:45)(Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:47)(Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelm(1-28)-NH₂; (SEQ ID NO:49)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:51)(A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:52)(Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:53)(Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:54)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:55)(Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:56)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:57)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:59)(Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:60)(Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:61)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:62)(Aib²,Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:63)(Aib²,Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:64)(Aib^(2,8),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:65)(Aib^(2,18),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:66)(Aib^(2,10),Glu(NH-hexyl)18)hGhrelin(1-28)-NH₂; (SEQ ID NO:67)(Aib2^(2,10),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:68)(Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:69)(Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:70)(Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:71)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:72)(Aib²,Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:73)(Aib²,Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:74)(Aib^(2,8),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:75)(Aib^(2,8),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:76)(Aib^(2,10),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:77)(Aib^(2,10),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ ID NO:78)(Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:79)(Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:80)(Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:81)(Glu(NH-hexyl)³,Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:82)(Aib²,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:83)(Aib²,Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:84)(Aib^(2,8),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:85)(Aib^(2,8),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:86)(Aib^(2,10),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:87)(Aib^(2,10),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:88)(Ac-Gly¹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:89)(Ac-Gly¹,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:90)(Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:91)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoy1)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:92) (Ac-Gly¹,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:93)(Ac-Gly¹,Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:94)(Ac-Gly¹,Dap(octanesulfonyl)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:95)(Ac-Gly¹,Dap(octanesulfonyl)³,Ser(n-octanoy1)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:96) (Ac-Gly¹,Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:97)(Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:98)(Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:99)(Ac-Gly¹,Glu(NH-hexyl)³, (Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:100) (Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:101) (Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoy1)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:102)(Ac-Gly¹,Aib²,G1u(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:103)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:104)(Ac-Gly¹,Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:105)(Ac-Gly¹,Aib²,4-Hyp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:105)(Ac-Gly¹,Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:105)(Ac-Gly¹,Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:105)(Ac-Gly¹,Aib²,Tic⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:105)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Thz⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Hyp⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:106)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂; (SEQID NO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:106) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:107)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:108) (Ac-Gly¹,Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:110)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:110) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQID NO:110) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:110) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:111)(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:112) (Ac-Gly¹,Aib⁸,Glu(NH-hexyl)¹⁷hGhrelin(1-28)-NH₂; (SEQ ID NO:113)(Ac-Gly¹,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:114)(Ac-Gly¹,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:114)(Ac-Gly¹,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:114)(Ac-Gly¹,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:114)(Ac-Gly¹,Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:115)(Ac-Gly¹,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:116)(Ac-Gly¹,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:116)(Ac-Gly¹,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:116)(Ac-Gly¹,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:116)(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:117)(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:118) (Ac-Gly¹,A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:119) (Ac-Gly¹,A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:120) (Ac-Gly¹,Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:121) (Ac-Gly¹,Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:122) (Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:123) (Ac-Gly¹,Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:124) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:125)(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)³,Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126) (Ac-Gly¹,Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:127) (Ac-Gly¹,Ser(n-octanoy1)¹⁵)hGhrelin(1-28)-NH₂; (SEQ ID NO:128)(Ac-Gly¹,Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQ ID NO:129)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:130) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:131) (Ac-Gly¹,Aib²,Glu(NH-hexyl)hu 3,15)hGhrelin(1-28)-NH₂; (SEQ IDNO:132) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQ IDNO:133) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂; (SEQID NO:134) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁵)hGhrelin(1-28)-NH₂; (SEQID NO:135) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,15))hGhrelin(1-28)-NH₂;(SEQ ID NO:136) (Ac-Gly¹,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:137) (Ac-Gly¹,Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ ID NO:138)(Ac-Gly¹,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ ID NO:139)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:140) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:141) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQ IDNO:142) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQ IDNO:143) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂; (SEQID NO:144) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁶)hGhrelin(1-28)-NH₂; (SEQID NO:145) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,16))hGhrelin(1-28)-NH₂;(SEQ ID NO:146) (Ac-Gly¹,Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:147) (Ac-Gly¹,Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:148)(Ac-Gly¹,Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ ID NO:149)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:150) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:151) (Ac-Gly¹,Aib²,Glu(NH˜hexyl)^(3,18))hGhrelin(1-28):NH₂; (SEQ IDNO:152) (Ac-Gly¹,Aib^(2,18),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:153) (Ac-Gly¹,Aib^(2,18),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂;(SEQ ID NO:154) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁸)hGhrelin(1-28)-NH₂;(SEQ ID NO:155)(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,18))hGhrelin(1-28)-NH₂; (SEQ IDNO:156) (Ac-Gly¹,Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:157)(Ac-Gly¹,Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:158)(Ac-Gly¹,Glu(NH-hexyl)^(3,9))hGhrelin(1-28)-NH₂; (SEQ ID NO:159)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:160) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:161) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ IDNO:162) (Ac-Gly¹,Aib^(2,18),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:163) (Ac-Gly¹,Aib^(2,18),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂;(SEQ ID NO:164) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:165)(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,19))hGhrelin(1-28)-NH₂; (SEQ IDNO:166) (Ac-Gly¹,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:167)(Ac-Gly¹,Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ ID NO:168)(Ac-Gly¹,Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ ID NO:169)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:170) (Ac-Gly¹,Aib²,Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:171) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ IDNO:172) (Ac-Gly¹,Aib^(2,18),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂; (SEQ IDNO:173) (Ac-Gly¹,Aib^(2,18),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂;(SEQ ID NO:174) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)²⁰)hGhrelin(1-28)-NH₂;(SEQ ID NO:175) or(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,20))hGhrelin(1-28)-NH₂; (SEQ IDNO:176)

or a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 5, wherein said compound is:(Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:21)(Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:22)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:23)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:24)(Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:25)(Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:26)(Dap(octanesulfonyl)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:27)(Dap(octanesulfonyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:28) (Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:29) (Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:30)(Cys(S-(CH₂)₉CH₃)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:31)(Glu(NH-hexyl)³,(Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:32)(Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:33)(Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:34)(Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:35)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,4-Hyp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Tic⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:37)(Aib²,Glu(NH-hexyl)^(3,7),Thz⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),4-Hyp⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:38)(Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:39)(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:41)(Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:42)(Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:43)(Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:44)(Aib⁸,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:45)(Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:46)(Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQ ID NO:47)(Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ ID NO:48)(Aib^(1,2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:49)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:51)(A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:52)(Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:53)(Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:54)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:55)(Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:56)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:57)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ac-Gly¹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:89)(Ac-Gly¹,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:90)(Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:91)(Ac-Gly¹,Glu(NH-hexyl)³, Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:92) (Ac-Gly¹,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:93)(Ac-Gly¹,Dap(octanesulfonyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:94)(Ac-Gly¹,Dap(octanesulfonyl)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:95)(Ac-Gly¹,Dap(octanesulfonyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:96) (Ac-Gly¹,Glu(NH-hexyl)³,Dap(octanesulfonyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:97)(Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:98)(Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:99)(Ac-Gly¹,Glu(NH-hexyl)³,(Cys(S-(CH₂)₉CH₃)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:100) (Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)³,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:101)(Ac-Gly¹,(Cys(S-(CH₂)₉CH₃)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:102) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:103) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:104) (Ac-Gly¹,Aib²,Thz⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,4-Hyp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,Dhp⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,Pip⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,Tic⁷,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:105) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Thz⁷)hGhrelin(1-28)-NH₂; (SEQID NO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Hyp⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:106)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Dhp⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Pip⁷)hGhrelin(1-28)-NH₂; (SEQID NO:106) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Tic⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:106) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:107)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:108) (Ac-Gly¹,Aib²,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:109) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:110)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:110) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQID NO:110) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂;(SEQ ID NO:110) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:111)(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:112) (Ac-Gly¹,Aib⁸,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:113) (Ac-Gly¹,Taz⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,3-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,4-Pal⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,2-Thi⁹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:114) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),Aib⁸)hGhrelin(1-28)-NH₂; (SEQ IDNO:115) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),Taz⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),3-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),4-Pal⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Gly¹,Glu(NH-hexyl)^(3,17),2-Thi⁹)hGhrelin(1-28)-NH₂; (SEQ IDNO:116) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:117) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:118) (Ac-Gly¹,A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:119) (Ac-Gly¹,A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQID NO:120) (Ac-Gly¹,Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:121) (Ac-Gly¹,Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:122) (Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:123) (Ac-Gly¹,Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:124) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:125) or(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)³,Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;;(SEQ ID NO:126)

or a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 6, wherein said compound is:(Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:21)(Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:22)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:23)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:24)(Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:35)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:39)(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:43)(Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:44)(Aib^(1,2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:49)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:51)(A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:52)(Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:53)(Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:54)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:55)(Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:56)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:57)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ac-Gly¹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:89)(Ac-Gly¹,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:90)(Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:91)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:92); (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:103) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:104) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:107) (Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQID NO:108) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQID NO:111) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:112) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:117)(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:118) (Ac-Gly¹,A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:119) (Ac-Gly¹,A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:120) (Ac-Gly¹,Glu(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:121) (Ac-Gly¹,Asp(1-heptanol)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:122) (Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:123) (Ac-Gly¹,Asp(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:124) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:125) or(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)³,Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126)

or a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 7, wherein said compound is:(Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:21)(Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:22)(Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:23)(Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:24)(Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:35)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:39)(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:43)(Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:44)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:51)(A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:52)(Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:36)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ac-Gly¹,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:89)(Ac-Gly¹,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:90)(Ac-Gly¹,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:91)(Ac-Gly¹,Glu(NH-hexyl)³,Ser(n-octanoyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:92) (Ac-Gly¹,Aib²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:103)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:104)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:107)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:108) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:111) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:112) (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:117)(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:118) (Ac-Gly¹,A5c²,Glu(NH-hexyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:119) (Ac-Gly¹,A5c²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:120) (Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:125) or(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)³,Lys(biotiny1)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126)

or a pharmaceutically acceptable salt thereof.
 9. A compound accordingto claim 1, wherein: A¹ is Ac-Gly, Ac-Aib or Aib; A² is Aib; A³ isGlu(NH-hexyl); A⁸ is Aib; A¹⁰ is Aib; and A¹⁷ is Glu(NH-hexyl) orLys(biotinyl); or a pharmaceutically acceptable salt thereof.
 10. Acompound according to claim 9, wherein: R¹ is NH₂; each of R² and R³ is,independently for each occurrence thereof, selected from the groupconsisting of H, Acyl, n-butyryl, isobutyryl and n-octanoyl; orpharmaceutically acceptable salts thereof.
 11. A compound according toclaim 10, wherein said compound is:(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib^(1,2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)(Ac-Gly¹,Aib²,Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:104)(Ac-Gly¹,Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:108) (Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂;(SEQ ID NO:112)(Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ IDNO:118)(Ac-Gly¹,Aib^(2,10),Glu(NH-hexyl)³,Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂;(SEQ ID NO:126) or (Aib^(2,10),Glu(NH-hexyl)^(3,7))hGhrelin(1-28)NH₂;(SEQ ID NO:179)

or pharmaceutically acceptable salts thereof.
 12. A compound accordingto claim 11, wherein said compound is:(Aib^(2,8),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:40)(Aib^(1,2.10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:50)(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58) and (Ac-Aib¹,Aib^(2,10),Glu(NH-hexyl)^(3,17))hGhrelin(1-28)-NH₂; (SEQ ID NO:118)

or pharmaceutically acceptable salts thereof.
 13. A compound accordingto claim 10, wherein said compound is:(Lys(biotinyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:58)

or a pharmaceutically acceptable salt thereof.
 14. A compound accordingto claim 1, wherein said compound is (Aib^(2,8), Ser³, Glu(NH-hexyl)¹⁷)hGrehlin(1-28)-NH₂ (SEQ ID NO:180)


15. A pharmaceutical composition comprising an effective amount of acompound according to claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or diluent.
 16. Amethod of screening for a compound able to bind to a GHS receptor, saidmethod comprising the step of measuring the ability of a compound toaffect binding of a compound according claim 1 to said receptor, to afragment of said receptor, to a polypeptide comprising said fragment ofsaid receptor, or to a derivative of said polypeptide.
 17. A method forstimulating growth hormone secretion in a subject in need of suchstimulation, comprising the step of administering to a subject aneffective amount of a ghrelin analog agonist according to claim 1, or apharmaceutically acceptable salt thereof, wherein said effective amountis at least an amount sufficient to produce a detectable increase ingrowth hormone secretion and, preferably, is an amount sufficient toachieve a beneficial affect in a patient.
 18. A method according toclaim 17 wherein said stimulation of growth hormone secretion isindicated for treatment of a growth hormone deficient state, forincreasing muscle mass, for increasing bone density, for sexualdysfunction in males or females, for facilitating a weight gain, forfacilitating maintenance of weight, for facilitating maintenance ofphysical functioning, for facilitating recovery of physical functionand/or facilitating appetite increase.
 19. A method according to claim18 wherein said facilitating weight gain, facilitating maintenance inweight, and/or facilitating appetite increase is indicated in a patienthaving a disease or disorder or undergoing a treatment accompanied byweight loss.
 20. A method according to claim 18 wherein said weight lossis due to onset of cachexia.
 21. A method according to claim 20 whereinsaid cachexia is incidental to said subject suffering from anorexia,bulimia, cancer, AIDS or chronic obstructive pulmonary disease.
 22. Amethod according to claim 19 wherein said weight loss is due to theonset of wasting syndrome
 23. A method according to claim 22 whereinsaid subject in need thereof suffering from wasting syndrome is frailand elderly.
 24. A method according to claim 19 wherein said weight lossis unexplained and wherein said subject is a healthy elder.
 25. A methodaccording to claim 19 wherein said weight loss is a precursor to theonset of Alzheimer's disease.
 26. A method according to claim 19 whereinsaid treatment accompanied by weight loss is selected from the groupconsisting of chemotherapy, radiation therapy, temporary immobilization,permanent immobilization and dialysis.
 27. A method of according toclaim 17 wherein said subject in need thereof is not suffering from adisease or disorder and is not undergoing a treatment accompanied byweight loss and is otherwise healthy.
 28. A method for achieving abeneficial affect in a subject comprising, said method comprising thestep of administering to said subject an effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein said effective amount is effective for producing a beneficialeffect in helping to treat or prevent post-operative ileus or chronicobstructive pulmonary disease.
 29. A method for suppressing growthhormone secretion in a subject in need of such suppression, comprisingthe step of administering to a subject an effective amount of a ghrelinanalog according to claim 1, or a pharmaceutically acceptable saltthereof, wherein said effective amount is at least an amount sufficientto produce a detectable decrease in growth hormone secretion and,preferably, is an amount sufficient to achieve a beneficial affect in apatient.
 30. A method according to claim 29 wherein said suppression ofgrowth hormone secretion is indicated for the treatment of a disease orcondition characterized by excessive growth hormone secretion, forfacilitation of loss of excessive body weight, for facilitation ofappetite decrease, for facilitation of weight maintenance, for treatingobesity, for treating diabetes, for treating complications of diabetesincluding retinopathy, and/or for treating cardiovascular disorders. 31.A method according to claim 30 wherein said excessive weight is acontributing factor to a disease or condition including hypertension,diabetes, dyslipidemia, cardiovascular disease, gall stones,osteoarthritis and cancers.
 32. A method according to claim 30 whereinsaid facilitation of loss of body weight reduces the likelihood of suchdiseases or conditions.
 33. A method according to claim 30 wherein saidfacilitation of loss of body weight comprises at least part of atreatment for such diseases or conditions.
 34. A method according toclaim 30 wherein said excessive weight is due to Prader-Willi syndrome.35. A compound according to formula (II):(R²R³)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶- A²⁷-A²⁸-R¹ (II)

wherein: A¹ is Gly, Acc, Aib, Ala, β-Ala or Gly(myristyl); A² is Ser,Abu, Acc, Act, Aib, Ala, Thr or Val; A³ is Ser, Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶),Ser(C(O)—R⁴), Thr(C(O)—R⁵) or HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); A⁴ isPhe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe,(X¹,X²,X³,X⁴,X⁵)Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr; A⁵ is Leu, Abu, Acc,Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle or Val; A⁶ is Ser, Abu,Acc, Act, Aib, Ala, Gly, Thr or Val; A⁷ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp,Inc, Ktp, Oic, Pip, Thz or Tic; A⁸ is Glu, Acc, Aib, Arg, Asn, Asp, Dab,Dap, Gln, Lys, Orn or HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); A⁹ is His, Acc,Aib, Apc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, (X¹,X²,X³,X⁴,X⁵—)Phe, Taz, 2-Thior 3-Thi; A¹⁰ is Gln, Acc, Aib, Asn, Asp or Glu; A¹¹ is Arg, Apc, hArg,Dab, Dap, Lys, Orn or HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); A¹² is Val, Abu,Acc, Aib, Ala, Cha, Nva, Gly, Ile, Leu, Nle or Tle; A¹³ is Gln, Acc,Aib, Asn, Asp or Glu; A¹⁴ is Gln, Acc, Aib, Asn, Asp or Glu; A¹⁵ is Arg,Acc, Aib, Apc, hArg, Dab, Dap, Lys, Om, Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷, Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) orHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); A¹⁶ is Lys, Acc, Aib, Apc, Arg, hArg,Dab, Dap, Orn, Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶),hCys(R¹⁷), Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷, Glu(O—R⁶),Ser(C(O)—R⁴), Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;A¹⁷ is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Asp(NH—R⁹),Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Lys(biotinyl), Lys(myristyl),Ser(C(O)—R⁴), Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted;A¹⁸ is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val, Asp(NH—R⁹), Asp(O—R⁸),Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹),Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵),HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted; A¹⁹ is Lys, Acc, Aib, Apc,Arg, hArg, Dab, Dap, Orn, Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵),hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷),Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O)or deleted; A²⁰ is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn,Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵), hCys(S—R¹⁶), hCys(R¹⁷),Dab(S(O)₂—R⁷), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷), Glu(O—R⁶), Ser(C(O)—R⁴),Thr(C(O)—R⁵), HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted; A²¹ is Pro,Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted; A²² isPro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;A²³ is Abu, Acc, Act, Aib, Ala, Apc, Gly, Nva, Val or deleted; A²⁴ isLys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn,HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted; A²⁵ is Leu, Abu, Acc, Aib,Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val or deleted; A²⁶ is Gln,Aib, Asn, Asp, Glu or deleted; A²⁷ is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc,Ktp, Oic, Pip, Thz, Tic or deleted; A²⁸ is Acc, Aib, Apc, Arg, hArg,Dab, Dap, Lys, Orn, HN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O) or deleted; R¹ is—OH, —NH₂, —(C₁-C₃₀)alkoxy or NH—X⁶—CH₂-Z⁰, wherein X⁶ is a(C₁-C₁₂)alkyl or (C₂-C₁₂)alkenyl and Z⁰ is —H, —OH, —CO₂H or —C(O)—NH₂;each of R² and R³ is, independently for each occurrence thereof,selected from the group consisting of H, (C₁-C₃₀)alkyl,(C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl,aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)alkyl,substituted (C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)acyl, substituted(C₂-C₃₀)alkenyl, substituted aryl(C₁-C₃₀)alkyl, substituted(C₂-C₃₀)alkynyl and substituted aryl(C₁-C₃₀)acyl or may be deleted; eachof R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is,independently for each occurrence thereof, selected from the groupconsisting of (C₁-C₄₀)alkyl, (C₂-C₄₀)alkenyl, substituted (C₁-C₄₀)alkyl, substituted (C₂-C₄₀) alkenyl, alkylaryl, substituted alkylaryl,aryl and substituted aryl; each of R¹² and R¹³ is, independently foreach occurrence, selected from the group consisting of H, (C₁-C₄₀)alkyl,(C₁-C₄₀)heteroalkyl, (C₁-C₄₀)acyl, (C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl,aryl(C₁-C₄₀)alkyl, aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)alkyl,substituted (C₁-C₄₀)heteroalkyl, substituted (C₁-C₄₀)acyl, substituted(C₂-C₄₀)alkenyl, substituted (C₂-C₄₀)alkynyl, substitutedaryl(C₁-C₄₀)alkyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl,—C(NH)—NH₂ and biotinyl; n is, independently for each occurrencethereof, 1, 2, 3, 4 or 5; each of X¹, X², X³, X⁴, and X⁵ is,independently for each occurrence thereof, selected from the groupconsisting of H, F, Cl, Br, I, (C₁₋₁₀)alkyl, substituted (C₁-C₁₀)alkyl,aryl, substituted aryl, OH, NH₂, NO₂ and CN; provided that: (I) when R²is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted (C₂-C₃₀)acyl, orsubstituted aryl(C₁-C₃₀)acyl, then R³ is H, (C₁-C₃₀)alkyl,(C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, aryl(C₁-C₃₀)alkyl, substituted(C₁-C₃₀)alkyl, substituted (C₂-C₃₀)heteroalkyl, substituted(C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl or substitutedaryl(C₁-C₃₀)alkyl; (II) when R¹² is (C₁-C₄₀)acyl, aryl(C₁-C₄₀)acyl,substituted (C₁-C₄₀)acyl, substituted aryl(C₁-C₄₀)acyl,(C₁-C₄₀)alkylsulfonyl, or —C(NH)—NH₂, then R¹³ is H or (C₁-C₄₀)alkyl,(C₁-C₄₀)heteroalkyl, (C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl,aryl(C₁-C₄₀)alkyl, substituted (C₁-C₄₀)alkyl, substituted(C₁-C₄₀)heteroalkyl, substituted (C₂-C₄₀)alkenyl, substituted(C₂-C₄₀)alkynyl, or substituted aryl(C₁-C₄₀)alkyl; (III) at least one ofA¹⁵, A¹⁶, A¹⁷, A¹⁸, A¹⁹ or A²⁰ of said ghrelin analog is selected fromthe group consisting of Asp(NH—R⁹), Asp(O—R⁸), Cys(S—R¹⁴), Cys(R¹⁵),hCys(S—R¹⁶), hCys(R¹⁷), Dab(S(O)₂—R¹¹), Dap(S(O)₂—R¹⁰), Glu(NH—R⁷),Glu(O—R⁶), Ser(C(O)—R⁴), Thr(C(O)—R⁵) andHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O); and (IV) when any of the groupconsisting of A¹⁵, A¹⁶, A¹⁷, A¹⁹ and A²⁰ isHN—CH((CH₂)_(n)—N(R¹²R¹³))—C(O), then R¹² must be biotinyl; or apharmaceutically acceptable salt thereof.
 36. A compound according toclaim 35, wherein: A¹ is Gly or Gly(myristyl); A² is Ser or Aib; A⁸ isGlu or Aib; and A¹⁷ is Ser(n-octanoyl) or Lys(myristyl); or apharmaceutically acceptable salt thereof.
 37. A compound according toclaim 36, wherein: A¹⁷ is Lys(myristyl) or a combination thereof.
 38. Acompound according to claim 37, wherein: R² is, independently for eachoccurrence thereof, selected from the group consisting of H, Acyl,n-butyryl, isobutyryl, n-octanoyl or myristyl; R³ is deleted; R⁴ isheptyl; R⁶ is hexyl; R⁷ is hexyl; R¹⁰ is octyl; R¹¹ is heptyl; and Accis, independently for each occurrence thereof, selected from the groupconsisting of A3c, A4c, A5c and A6c; or a pharmaceutically acceptablesalt thereof.
 39. A compound according to claim 36, wherein saidcompound is: (Aib², Lys(myristyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ ID NO:177)or (Gly(myristyl)¹, Aib², Lys(myristyl)¹⁷)hGhrelin(1-28)-NH₂; (SEQ IDNO:178) or or a pharmaceutically acceptable salt thereof.
 40. Apharmaceutical composition comprising an effective amount of a compoundof according to claim 35, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier or diluent.
 41. A method ofscreening for a compound able to bind to a GHS receptor, said methodcomprising the step of measuring the ability of a compound to affectbinding of a compound according to claim 35 to said receptor, to afragment of said receptor, to a polypeptide comprising said fragment ofsaid receptor or to a derivative of said polypeptide.
 42. A method forachieving a beneficial affect in a subject comprising, said methodcomprising the step of administering to said subject an effective amountof a compound according to claim 35, or a pharmaceutically acceptablesalt thereof, wherein said effective amount is effective for producing abeneficial effect in helping to treat or prevent a disease or disorder.43. A method for stimulating growth hormone secretion in a subject inneed of such stimulation, comprising the step of administering to asubject an effective amount of a ghrelin analog agonist according toclaim 35, or a pharmaceutically acceptable salt thereof, wherein saideffective amount is at least an amount sufficient to produce adetectable increase in growth hormone secretion and, preferably, is anamount sufficient to achieve a beneficial affect in a patient.
 44. Amethod according to claim 43 wherein said stimulation of growth hormonesecretion is indicated for treatment of a growth hormone deficientstate, for increasing muscle mass, for increasing bone density, forsexual dysfunction in males or females, for facilitating a weight gain,for facilitating maintenance of weight, for facilitating maintenance ofphysical functioning, for facilitating recovery of physical functionand/or facilitating appetite increase.
 45. A method according to claim44 wherein said facilitating weight gain, facilitating maintenance inweight and/or facilitating appetite increase is indicated in a patienthaving a disease or disorder or undergoing a treatment which isaccompanied by weight loss.
 46. A method according to claim 45 whereinsaid weight loss is due to the onset of cachexia.
 47. A method accordingto claim 46 wherein said cachexia is incidental to said subjectsuffering from anorexia, bulimia, cancer, AIDS or chronic obstructivepulmonary disease.
 48. A method according to claim 45 wherein saidweight loss is due to the onset of wasting syndrome
 49. A methodaccording to claim 48 wherein said subject in need thereof sufferingfrom wasting syndrome is frail and elderly.
 50. A method according toclaim 45 wherein said weight loss is unexplained and wherein saidsubject is a healthy elder.
 51. A method according to claim 45 whereinsaid weight loss is a precursor to the onset of Alzheimer's disease. 52.A method according to claim 45 wherein said treatment accompanied byweight loss is selected from the group consisting of chemotherapy,radiation therapy, temporary immobilization, permanent immobilizationand dialysis.
 53. A method of according to claim 43 wherein said subjectin need thereof is not suffering from a disease or disorder and is notundergoing a treatment accompanied by weight loss and is otherwisehealthy.
 54. A method for achieving a beneficial affect in a subjectcomprising, said method comprising the step of administering to saidsubject an effective amount of a compound according to claim 35, or apharmaceutically acceptable salt thereof, wherein said effective amountis effective for producing a beneficial effect in helping to treat orprevent post-operative ileus or chronic obstructive pulmonary disease.55. A method for suppressing growth hormone secretion in a subject inneed of such suppression, comprising the step of administering to asubject an effective amount of a ghrelin analog according to claim 35,or a pharmaceutically acceptable salt thereof, wherein said effectiveamount is at least an amount sufficient to produce a detectable decreasein growth hormone secretion and, preferably, is an amount sufficient toachieve a beneficial affect in a patient.
 56. A method according toclaim 54 wherein said suppression of growth hormone secretion isindicated for the treatment of a disease or condition characterized byexcessive growth hormone secretion, for facilitation of loss ofexcessive body weight, for facilitation of appetite decrease, forfacilitation of weight maintenance, for treating obesity, for treatingdiabetes, for treating complications of diabetes including retinopathyand/or for treating cardiovascular disorders.
 57. A method according toclaim 55 wherein said excessive weight is a contributing factor to adisease or condition including hypertension, diabetes, dyslipidemia,cardiovascular disease, gall stones, osteoarthritis and cancers.
 58. Amethod according to claim 55 wherein said facilitation of loss of bodyweight reduces the likelihood of such diseases or conditions.
 59. Amethod according to claim 56 wherein said facilitation of loss of bodyweight comprises at least part of a treatment for such diseases orconditions.
 60. A method according to claim 56 wherein said excessiveweight is due to Prader-Willi syndrome.
 61. A method of treatinginflammation in a subject comprising administering to the subject aneffective amount of a compound according to claim
 1. 62. The method ofclaim 61, wherein the inflammation is associated with an infectiousprocess.
 63. The method of claim 62, wherein the infectious process is aviral infection selected from the group consisting of Herpes simplexvirus type-1, Herpes simplex virus type-2, Cytomegalovirus, Epstein-Barrvirus, Varicella-zoster virus, Human herpesvirus 6, Human herpesvirus 7,Human herpesvirus 8, Variola virus, Vesicular stomatitis virus,Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis Dvirus, Hepatitis E virus, Rhinovirus, Coronavirus, Influenza virus A,Influenza virus B, Measles virus, Polyomavirus, Human Papilomavirus,Respiratory syncytial virus, Adenovirus, Coxsackie virus, Dengue virus,Mumps virus, Poliovirus, Rabies virus, Rous sarcoma virus, Yellow fevervirus, Ebola virus, Marburg virus, Lassa fever virus, Eastern EquineEncephalitis virus, Japanese Encephalitis virus, St. Louis Encephalitisvirus, Murray Valley fever virus, West Nile virus, Rift Valley fevervirus, Rotavirus A, Rotavirus B, Rotavirus C, Sindbis virus, SimianImmunodeficiency virus, Human T-cell Leukemia virustype-1, Hantavirus,Rubella virus, Simian Immunodeficiency virus, Human Immunodeficiencyvirus type-1 and Human Immunodeficiency virus type-2.
 64. The method ofclaim 62, wherein the infectious process is a bacterial infectionselected from the group consisting of M. tuberculosis, M. bovis, M.bovis strain BCG, BCG substrains, M. avium, M. intracellulare, M.africanum, M. kansasii, M. marinum, M. ulcerans, M. avium subspeciespara tuberculosis, Nocardia asteroides, other Nocardia species,Legionella pneumophila, other Legionella species, Salmonella typhi,other Salmonella species, Shigella species, Yersinia pestis, Pasteurellahaemolytica, Pasteurella multocida, other Pasteurella species,Actinobacillus pleuropneumoniae, Listeria monocytogenes, Listeriaivanovii, Brucella abortus, other Brucella species, Cowdria ruminantium,Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia psittaci,Coxiella burnetti, other Rickettsia species, Ehrlichia species,Staphylococcus aureus, Staphylococcus epidermidis, Streptococcuspyogenes, Streptococcus agalactiae, Bacillus anthracis, Escherichiacoli, Vibrio cholerae, Campylobacter species, Neiserria meningitidis,Neiserria gonorrhea, Pseudomonas aeruginosa, other Pseudomonas species,Haemophilus influenzae, Haemophilus ducreyi, other Hemophilus species,Clostridium tetani, other Clostridium species, Yersinia enterolitica andother Yersinia species.
 65. The method of claim 62, wherein theinfectious process is a parasitic infection selected from the groupconsisting of Toxoplasma gondii, Plasmodium, Trypanosoma brucei,Trypanosoma cruzi, Leishmania, Schistosoma and Entamoeba histolytica.66. The method of claim 62, wherein the infectious process is a fungalinfection selected from the group consisting of Candida albicans,Cryptococcus neoformans, Histoplama capsulatum, Aspergillus fumigatus,Coccidiodes immitis, Paracoccidiodes brasiliensis, Blastomycesdermitidis, Pneomocystis carnii, Penicillium marneffi and Alternariaalternata.
 67. The method of claim 61, wherein said inflammation isassociated with liver toxicity.
 68. The method of claim 67, wherein saidliver toxicity is associated with cancer therapy.
 69. The method ofclaim 68, wherein said cancer therapy is apoptosis induction.
 70. Themethod of claim 68, wherein said cancer therapy is chemotherapy.
 71. Themethod of claim 68, wherein said cancer therapy is a combination ofchemotherapy and apoptosis induction.
 72. The method of claim 61,wherein the inflammation is associated with an inflammatory disease. 73.The method of claim 72, wherein the inflammatory disease is selectedfrom the group consisting of asthma, reactive arthritis, hepatitis,spondyarthritis, Sjogren's syndrome, Alzheimer's disease and atopicdermatitis.
 74. The method of claim 72, wherein the inflammatory diseaseis associated with an autoimmune disease.
 75. The method of claim 74,wherein the autoimmune disease is systemic lupus erythematosus,rheumatoid arthritis, systemic vasculitis, insulin dependent diabetesmellitus, multiple sclerosis, muscular dystrophy, experimental allergicencephalomyelitis, psoriasis, Crohn's disease, inflammatory boweldisease, ulcerative colitis, Addison's disease, alopecia aretea, celiacdisease, thyroid disease and scleroderma.
 76. The method of claim 61,wherein the inflammation is associated with a bum.
 77. The method ofclaim 61, wherein the inflammation is associated with lung inflammation.78. The method of claim 61, wherein the inflammation is associated withcancer.
 79. The method of claim 78, wherein the cancer is selected fromthe group consisting of lymphoma, leukemia, mycosis fungoide, carcinoma,adenocarcinoma, sarcoma, glioma, blastoma, neuroblastoma, plasmacytoma,histiocytoma, melanoma, adenoma, hypoxic tumor, myeloma, AIDS-relatedlymphoma or AIDS-related sarcoma, metastatic cancer, bladder cancer,brain cancer, nervous system cancer, glioblastoma, ovarian cancer, skincancer, liver cancer, squamous cell carcinomas of the mouth, throat,larynx, and lung, colon cancer, cervical cancer, breast cancer,epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer,esophageal carcinoma, head and neck carcinoma, hematopoietic cancer,testicular cancer, colo-rectal cancer, prostatic cancer and pancreaticcancer.
 80. The method of claim 61, wherein the inflammation isassociated with transplant rejection.
 81. A method of treating loss ofappetite caused by an inflammation in a subject by administering to thesubject an effective amount of a compound according to claim
 1. 82. Themethod of claim 81 wherein the inflammation is low grade inflammation.83. The method of claim 82 wherein the low grade inflammation is causedby aging.